Topically administered strontium-containing complexes for treating pain, pruritis and inflammation

ABSTRACT

The present disclosure consists of therapeutically-active compositions that combine strontium with at least one additional molecules that increase the overall therapeutic potency of the combination beyond the potency of any of the separate constituents. Specifically, the combinations described herein perform two important functions; (1) they increase the ability of topically-applied strontium to inhibit both acute sensory irritation (e.g., pruritus and pain), redness, swelling and inflammation (collectively defined for purposes of this description, “irritation”) and the chronic irritation that is characteristic of and contributes to the development and maintenance of painful or pruritic neuropathic conditions; and (2) they decrease the strontium activated pathways that are known to enhance the development and maintenance of pain, pruritis and neuropathic conditions.

TECHNICAL FIELD

The present disclosure consists of therapeutically-active compositionsthat combine strontium with at least one additional molecules thatincrease the overall therapeutic potency of the combination beyond thepotency of any of the separate constituents. Specifically, thecombinations described herein perform two important functions; (1) theyincrease the ability of topically-applied strontium to inhibit bothacute sensory irritation (e.g., pruritus and pain), redness, swellingand inflammation (collectively defined for purposes of this description,“irritation”) and the chronic irritation that is characteristic of andcontributes to the development and maintenance of painful or pruriticneuropathic conditions; and (2) they decrease the strontium activatedpathways that are known to enhance the development and maintenance ofacute pain and pruritis, and neuropathic conditions.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,716,625 describes the ability of topically-appliedstrontium, in divalent ionic form, to rapidly suppress acute sensoryirritation (e.g., stinging, burning pain and/or itching) andaccompanying inflammation due to chemical irritants, electromagneticradiation, “environmental irritants” and diseases (strontium's“anti-irritant activity”).

While not being bound or otherwise limited by any particular biochemicalmechanism, it was theorized that strontium's anti-irritant activity wasdue to the ability of strontium to selectively suppress activation ofType C Nociceptors (TCN), the only sensory nerves that produce andtransmit stinging, burning pain and itching sensations and theneurogenic inflammatory response that can accompany TCN activation.

When compared to the existing topical drugs able to suppress suchsensory irritation like lidocaine or Novocain™, the local anesthetictypically used by dentists during dental procedures, strontium has aunique property—it is highly selective for only the TCN and doesn'tsignificantly affect the many other sensory nerves that provide normaltactile sensations and “cutaneous awareness.” Since lidocaine and othertopical local anesthetics lack this specificity for TCN, they can causenumbness and loss of function.

While topically applied strontium can rapidly inhibit the activation ofTCN sensory nerve subsets that transmit sensations of pain (e.g.,burning and stinging) and pruritus (itching), recent investigations tounderstand strontium's anti-irritant mechanisms surprisingly reveal thatstrontium also has negative effects on several biochemical pathways thattend to negate the positive anti-irritant benefits of strontium fortreatment of neuropathic conditions.

Therefore it is desirable to create new strontium-containing molecules,complexes and formulations that increase the “positive” therapeuticbenefits of strontium and decrease the “negative” effects of strontiumon acute pain, pruritis and neuropathic conditions

SUMMARY OF THE INVENTION

In accordance with the teachings herein, the present disclosure relatesgenerally to compositions of strontium-containing complexes in asuitable carrier vehicle.

The complexes are bipartite or tripartite in nature, in that theyinclude at least one or two different components: divalent cationicstrontium, and at least one counterion, such as a polyhydroxyphenol oran aromatic amino acid. In the form of a tripartite composition, thecomplexes include divalent cationic strontium, at least onepolyhydroxyphenol, and at least one cysteine-based antioxidant.

The cysteine-based anti-oxidant may be selected from the groupconsisting of: cysteine, cystine, N-acetyl cysteine (NAC), N-acetylcysteinate, N-acetyl cystine and N,S-diacetylcysteine, or mixturesthereof.

In addition, the polyhydroxyphenol may be selected from the groupconsisting of: gallic acid, caffeic acid, quercetin, luteolin,epigallocatechin gallate, epigallocatechin, epicatechin gallate,genistein and myricetin, or mixtures thereof. In one embodiment thepolyhydroxyphenol is a mixture of gallic acid and caffeic acid.

Either the bipartite or tripartite complexes may also be complexed witha polymer, such as a polyanionic polymer. This polymer may be s selectedfrom the group consisting of: polyvinylpyrrolidone (PVP), cyclodextrins,carragenans, alginic acid, xanthan gum, sulfated polysaccharides,pentosan polysulfate, chondroitin sulfate, dextran sulfate and heparinsulfate.

The osmolarity of the compositions may beneficially have high osmoticacitivity, such as having an osmolarity equal to or greater than 400mOsm, or between 400 and 2000 mOsm.

The polyhydroxyphenol(s) is (are) in essentially pure form when added tothe compositions described herein, or is (are) added in the form of aplant extract, such as green tea or soy extract.

In an alternate embodiment of a tripartite composition, the at least onecysteine-based anti-oxidant and the at least one polyhydroxyphenol areconjugated together by a cleavable bond, such as a peptide bond, anester bond, a thioester bond, an enzymatically cleavable bond, adisulphide bond, or a pH dependent bond.

In an alternate embodiment of a bipartite composition, the divalentcationic strontium is complexed with at least one polyhydroxyphenol (asdescribed above), and the complex is placed in a suitable carriervehicle prior to administration.

In yet another embodiment of the bipartite composition, the divalentcationic strontium is complexed with an aromatic amino acid, and thecomplex is placed in a suitable carrier vehicle prior to administration.Such amino acids include, for example, histidine, tyrosine,phenylalanine and tryptophan, and are in one embodiment in the L isomerform.

The compositions containing bipartite complexes can also include otherconstituents, such as any of the aforementioned strontium counterions.

Other aspects of the invention are found throughout the specification.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure consists of therapeutically-active compositionsthat combine strontium with at least one additional molecules thatincrease the overall therapeutic potency of the combination beyond thepotency of any of the separate constituents. Specifically, thecombinations described herein perform two important functions; (1) theyincrease the ability of topically-applied strontium to inhibit bothacute sensory irritation (e.g., pruritus and pain), redness, swellingand inflammation (collectively defined for purposes of this description,“irritation”) and the chronic irritation that is characteristic of andcontributes to the development and maintenance of painful or pruriticneuropathic conditions; and (2) they decrease the strontium activatedpathways that are known to enhance the development and maintenance ofacute pain and pruritis, and neuropathic conditions.

Accordingly, the present disclosure relates, in part, to compositionsthat include complexes of divalent strontium, and at least twocounterions—a cysteine based anti-oxidant and a polyphenolic compound,both of which are discussed in greater detail below.

Another aspect of the present disclosure relates to compositions thatinclude complexes of divalent strontium and at least onepolyhydroxyphenolic compound.

In yet another aspect of the present disclosure relates to compositionsthat include complexes of divalent strontium and at least one aminoacid.

In the description that follows, a number of terms are extensivelyutilized. In order to provide a clear and consistent understanding ofthe specification and claims, including the scope to be given suchterms, the following non-limiting definitions are provided.

When the terms “one,” “a,” or “an” are used in this disclosure, theymean “at least one” or “one or more,” unless otherwise indicated.

The term “skin” refers to external surfaces of the body in the broadestsense of the word and therefore implicitly includes all keratinized skinas well as, for example, the epithelial surfaces of the eye, therespiratory tract, the gastrointestinal tract and the genitourinarytract, including the cervix and the vagina.

The term “salt” as used herein refers to the common chemical definitionof salt—that is, a compound that is composed of ionic, chargedsubstances (atoms and/or molecules) that combine to form an electricallyneutral compound having no net electrostatic charge.

The term “complex” as used herein refers to a combination of thestrontium cation and two other negatively charged or polar molecules(strontium counterions) via either electrostatic forces (for example,due to the pi-electrons in the phenolic ring structures), or associationwith a partial negative charge or other inter-molecular charges. Inaddition to strontium and the two strontium counterions, the complex mayalso contain polymeric substances like polyvinylpyrrolidones,polyacrylamides, polyanionic polymers like alginic acid, carrageenans orcarbohydrate polymers that have an inherent ability to reversably bindto and complex with thiol-containing molecules like N-Acetyl-L-Cysteine(NAC), or polyhydroxyphenolic compounds like gallic acid, quercetin,leuteolin, myricetin and other similar molecules.

The term “cysteine-based” anti-oxidant as used herein refers tocysteine, cysteine derivatives, cysteine-containing small (less thanfour amino acids) peptides and cysteine precursors.

The term “cleavable” means a covalent chemical bond that is capable ofbeing broken. “Cleavable” only requires that a fraction of the chemicalbonds are cleaved, that is, the chemical bonds are cleavable if aportion of the bonds are cleaved. In one instance, the bond is cleavablewithin the skin after administration.

The term “conjugated” means a compound where at least two of thecomponents are joined together with a cleavable bond.

The term “neuropathic” as used herein is used interchangeably with“chronic”, and includes neuropathic pain, neuropathic pruritis, andneuropathic itching. It is recognized that neuropathic conditions aretypically accompanied by nerve damage. Exemplary neuropathic conditionsinclude, for example, chemotherapy-induced neuropathy, complex regionalpain syndrome, HIV sensory neuropathy, neuropathy secondary to tumorinfiltration, painful diabetic neuropathy, phantom limb pain,postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia,central post-stroke pain, multiple sclerosis pain, parkinson diseasepain and spinal cord injury pain.

Other pain-associated terminology may include the following:

TABLE I Pain Term Definition Allodynia Pain due to a stimulus that doesnot normally provoke pain Analgesia Absence of pain in response tostimulation that is normally painful Hyperalgesia An increased responseto a stimulus that is normally painful Hyperesthesia Increasedsensitivity to stimulation, excluding the special senses Hyperpathia Apainful syndrome characterized by an abnormally painful reaction to astimulus, especially a repetitive stimulus, as well as an increasedthreshold Hypoalgesia Diminished pain in response to a normally painfulstimulus Hypoesthesia Decreased sensitivity to stimulation, excludingthe special senses

Strontium's Anti-Irritant & Anti-Inflammatory Activity Can Be GreatlyEnhanced

It has been surprisingly discovered that the reason strontium isfrequently unable to completely block pain, itching or inflammation isdue to two factors: (1) the limited amount of strontium that can betopically applied, after which the hyperosmotic effects of the strontiumsalts themselves start to cause pain, itching or inflammation. This isdue to the fact that strontium has a relatively low potency in itsability to suppress pain, itching and inflammation compared to manyother drugs with similar therapeutic goals; and (2) the ability ofstrontium to stimulate pathways that may act to negate strontium'sinherent anti-irritant activities, thus reducing the overall therapeuticbenefit. The degree to which strontium will negate its anti-irritantbenefits depends on many factors related to the type of nerve damagethat caused the neuropathic condition to develop (e.g., viral infection,physical trauma such as amputation or nerve compression, metabolic nervedamage as occurs in diabetes, coexisting inflammation and other factors.

For example, commonly used non-steroidal anti-inflammatory drugs (NSAID)like aspirin, ibuprofen and naproxen are typically used at oral doses ofseveral hundred milligrams and provide an effective reduction of manytypes of inflammation-associated pain. Opioid pain relievers such aslevorphanol, oxymorphone, oxycodone and hydrocodone arepharmacologically related to codeine, morphine and heroin and provideeffective pain relief at oral doses in the range of 2 mg to about 10 mgper dose. In contrast, orally administered strontium salts such asstrontium ranelate, an oral drug approved for the treatment andprevention of osteoporosis, is approved in over 70 countries, and isadministered at a dose of 2,000 mg per day. Since strontium ranelate isa simple salt of strontium, it yields 680 mg of elemental strontium uponcontact with water or gastric fluids. However, even at this high dose ofpure elemental strontium, there are no reports of the ability to reducepain or inflammatory reactions.

It has been determined that topical strontium has the ability to reducepain, pruritus and inflammation due to the fact that topicalformulations can deliver thousands of times higher strontiumconcentrations then can be achieved by oral, systemic administration.Even at the relatively high local concentrations that can be achievedtopically when administered to the skin, the effect of strontium on keybiochemical pathways that cause pain, pruritus and inflammation is onlypartial. For example, if the activity of a hypothetical pain oritch-producing pathway is inhibited by 90% to 100%, a patient reportsthat their pain or itching was completely stopped. In contrast,topically-applied strontium may only inhibit that pathway by 40% to 50%,sufficient inhibition for a patient to observe that the pain or itchingwas clearly reduced, but still present and still bothersome.

The Skin Senses Danger by Activation of Multiple Molecular Sensors

The skin senses potentially harmful chemicals by two classes of nerves,called nociceptors, that form a “sensory web” just under the surface ofthe skin. A-delta nerves respond to physical trauma by transmitting apain sensation with a sharp, pricking quality. Type C nerves (TCN) arechemical sensors that respond to irritants from our environment,microbes, temperature extremes, ionizing radiation and allergic andnon-allergic skin conditions and transmit diffuse sensations of burning,stinging pain or itching (“irritation”). When excessively stimulated,TCN can also release neuropeptides (e.g., Substance P) that directlyactivate histamine-containing mast cells and and attract and activateother immune system cells such as neutrophils that cause redness,swelling and even local skin damage. After activation by irritanttriggers in the skin, both nociceptors synapse near the spinal cord inthe dorsal root ganglia (DRG) and release neurotransmitters thatactivate nerve pathways that relay signal to the brain where theirritant quality of the sensations is consciously appreciated.

Acute, Chronic & Neuropathic Pain & Pruritus Occur Upon NociceptorActivation

Upon activation, both types of nociceptors may be activated or in manyinstances either the A-delta or TCN are preferentially activated. Sinceonly the TCNs extend to the outermost portions of the epidermis and maybe activated by virtually any process that changes the localbiochemistry of the epidermis, TCNs are preferentially activated inresponse to most irritating stimuli. Upon activation of TCNs in theskin, the TCNs transmit a signal to the spinal cord and triggerneurotransmitter release in the DRG that activate nerves in the spinalcord that relay the pain and itch signals to the brain. Acute activationof TCNs that is caused by exposure to a chemical irritant, trauma or asunburn typically causes painful or pruritic sensations that last onlyseveral days and is termed “nociceptive pain”. When the stimulus isprolonged or excessively severe as can occur after a viral disease likeshingles or HIV, or the nerves are damaged by trauma to nerves fromphysical pressure, thermal burns, diabetes or extensive physical traumato a limb, painful sensations or pruritus can continue for many years.Such chronic pain or pruritus caused by excessive nociceptor activationor damage is termed “neuropathic” and is among one of the most difficultconditions to treat. Even the best oral or topical drugs have only avery limited therapeutic benefit and many have substantial side effectsthat limit their use.

Nociceptive Signals are Typically Encoded as Precisely-Timed Changes ofIntracellular Calcium Concentration that Travel as “Calcium Waves”within Nociceptors

No matter what causes nociceptor activation, the event is encoded into auniversal code; a complex change in the intracellular calciumconcentration that, in turn, is transmitted throughout the nociceptor.Calcium thus acts as a universal “second messenger” and informationtransmitted by a nociceptor, including the intensity and quality of painor pruritus is converted into a language made up of rapidly changingcalcium concentrations. Since nerves in general and nociceptors inparticular transmit their calcium code typically within about1/1000^(th) of a second, the timing and spatial distribution of calciummust be exquisitely regulated to accurately transmit the encodedinformation. In virtually all nerves, including nociceptors, theintensity of the signal (e.g., the severity of pain or pruritus) isencoded as a change in frequency of neurotransmitters that are releasedinto the synapse and activate post-synaptic nerves that relay theinformation ultimately to the brain. The higher the frequency, the moreintense the perceived sensation. When a nociceptor is activated, thecalcium signal is transmitted through multiple biochemical pathways,many of which operate in sequence such that the output of one pathwaybecomes the input of the next.

Nociceptive Signals and the Biochemical Pathways that Encode SignalsHave an Output that is Logarithmically Related to the Input

The many nociceptor pathways as well as the overall neurotransmitterrelease by a nociceptor is typically logarithmically related to theintensity of the stimulus. For example, if the irritant caused thenociceptor activation to increase its frequency of activation, alsocalled depolarization, from 10 to 50 per second, the frequency of theresultant neurotransmitter release may only increase by a factor of 1.7(Log 10=1.0; Log 50=1.7). This fact is particularly relevant since itsuggests that a relatively small amount of inhibition of a nociceptor'sactivation can cause a large reduction in the perceived severity of thepainful or pruritic stimulus. Since their are many separate pathways innociceptors that act in sequence to encode and transmit the irritantstimulus, inhibiting each of the sequential pathways at one or more of apathway's steps has the potential to produce a very large cumulativereduction of the painful or pruritic sensation.

Current strontium-containing formulations typically use strontiumnitrate or strontium chloride hexahydrate as the strontium source. Sinceneither the nitrate or chloride anions contribute to strontium's abilityto reduce pain or pruritus, they only act to increase the osmolarity ofthe formulation. Recent research has demonstrated that high osmolarityformulations activate specific osmotic sensors present on nociceptors,keratinocytes and immune or inflammatory cells that can activatenociceptors. An example of this is the “salt in the wound” effect thatcauses stinging and burning if a concentrated solution of a simple saltis poured into wound. In addition to causing discomfort, high osmolaritysolutions can directly activate inflammatory cells and cause them torelease chemicals that cause nociceptor activation. It is thereforedesirable to eliminate as many “non-active” components of the strontiumsalt or complex to minimize the potential for osmotic-induced nociceptoractivation and inflammation.

Strontium Alters the Dynamics and Spatial Distribution of Calcium Waves

Strontium's unique therapeutic properties are due to its chemicalresemblance to calcium, the most important and universal “secondmessenger” in nerves and in all other cells that regulate virtually allcellular functions. The calcium ion always has two positive charges andits ionic radius is 0.99 angstroms, about the size of a hydrogen atom.Of all the elements, strontium most closely resembles calcium, since italso only exists as a divalent positively-charged ion and has an ionicradius of 1.13 angstroms. For this reason, strontium typically binds tocalcium-binding sites and mimics calcium's activity. Most often astrontium-induced response is less potent and may be as low as about1/1000^(th) as active as calcium, but more often, strontium has activitythat is nearly the same as calcium or in the range of 1/10^(th) to1/30^(th) as active as calcium. In other calcium-dependent activities,strontium can be more active than calcium, for example. It isstrontium's calcium-mimetic activity that enables strontium to produceits many and varied activities. Since calcium is critical for so manycellular functions, if it were strongly inhibited the effects would betoxic to a cell. In contrast, since strontium can typically substitutefor calcium, albeit with lower activity, the activity of thecalcium-dependent pathway will not be shut down. Instead, the pathwayactivity will be reduced, similar to turning down the volume control ofa radio. Since strontium, in a metaphoric sense, only turns down thevolume control of calcium-dependent pathways rather than shutting downsuch pathways, the chances of significant adverse reactions or toxicityis much reduced compared to a drug that completely blocks a pathway.

When irritants from chemicals, disease, trauma or other exposuresactivate receptors on the surface of TCNs that encode the intensity oftheir response as rapid changes in intracellular calcium concentrations,these changes can occur in less then 1/1000th of a second and producehighly complex “waves” of changing calcium concentration that propagatethrough the nerve and trigger most, if not all, of the pathways thatcause acute, chronic and neuropathic irritation. In addition to thefrequency of calcium waves, alterations in the dynamics of calciumconcentration change the duration, magnitude and the precise shape ofthe calcium waveform that alters the coexisting electrostatic field thatis a critical regulator of TCN activity. These changes independentlyactivate the release of multiple inflammatory mediators, includingprostaglandins (e.g., PGE2), leukotrienes (e.g., LTB4, C4, D4 & E4) andreactive oxygen species (ROS) including superoxide, hydrogen peroxide,hydroxyl radicals, hypochlorous acid and peroxynitrite.

Strontium thus significantly alters the pain and itch sensations encodedwithin calcium waves present in painful and pruritic neuropathicconditions, and has the effect of garbling the signal and reducing itsperceived intensity by the brain. Due to strontium binding to multiplecalcium-dependent signaling pathways, strontium significantly alterscalcium-encoded signals by multiple independent mechanisms. Some of thecalcium-dependent kinases are known to be essential for the developmentof neuropathic conditions, since their inhibition in animal models canprevent and or reverse established neuropathic conditions.

Strontium is not able to bind effectively to the calcium bindingproteins within the cytoplasmic interior of nociceptors that normallyremove calcium within less than a millisecond after calcium enters thenociceptor, thus producing a transient increase in calcium concentrationthat contributes to the precisely-timed calcium waves. Strontium is alsomuch less effectively pumped into and released from a nociceptor'sprimary calcium storage site, the endoplasmic reticulum (ER). When anociceptor-activating signal is received, strontium inhibits thecalcium-induced calcium release (CICR) pathway that amplifies thecalcium signal, and strontium does not have the ability to regulateinositol triphosphate (IP₃)-induced calcium release by acting to inhibitadditional calcium release if the concentration of calcium in thecytoplasm is too high.

Once calcium enters a nociceptor during its activation anddepolarization, it activates the release of a massive amount of calciumthat is stored in the ER by the CICR pathway. This mechanism has theeffect of greatly amplifying the amount of calcium that is available toform a wave and to regulate calcium-dependent pathways. Strontium isover a hundred-fold less active than calcium in its ability to induceCICR and thus significantly alters the calcium concentration changesthat normally occur in response to irritants. When in the ER, strontiumalso binds much less avidly to the ER calcium binding proteins that actas buffers and sequester the free calcium until it is released by CICRor other similar mechanisms. As a result, strontium reaches aconcentration of more than 150% greater than calcium and displacescalcium from performing it's amplifying function during CICR. Strontiumis also much less active then calcium in regulating a second importantcalcium amplifying mechanism triggered by IP₃, a ubiquitous substancethat also activates calcium release from the ER by an IP₃-specificreceptor. At low concentrations of calcium, IP₃ acts as a potentstimulator of calcium release that acts to amplify the much smallercalcium influx during depolarization. When the calcium concentration issufficiently elevated, calcium acts to inhibit further calcium releasethus maintaining the calcium concentration within a limitedconcentration range. When strontium is present, it can mimic calcium inits ability to activate IP₃-induced calcium release, but strontium isnot able to inhibit excessive calcium release causing both calcium andstrontium to reach higher concentrations over an extended time.Strontium's ability to completely inhibit calcium-induced release due toIP₃ is particularly important, since IP₃-induced calcium release isknown to be responsible for generation of calcium waves. These types ofstrontium effects significantly change the calcium dynamics and calciumwaveforms associated with neuropathic conditions, and thus contribute tostrontium's suppressive effects on pain and pruritis.

Strontium Inhibits Calcium-Dependent Neurotransmitter Release

While strontium also affects additional pathways that control thedynamics of calcium within nociceptors, there is one strontium-inducedinterference with calcium-dependent transmission of pain anditch-encoded calcium waves that is critically important for suppressionof both acute, chronic and neuropathic conditions. That is, the abilityof strontium to bind and inactivate synaptotagmin-1, a molecule that isprincipally responsible for neurotransmitter release in the DRG andrelease of inflammatory neuropeptides, including substance P from theperipheral portion of a TCN in the skin. Substance P is known to be themost important inflammatory neuropeptide released from TCNs thatactivates virtually every inflammatory immune “white blood cell” (WBC),including mast cells that contain histamine and over 50 differentinflammatory chemicals, including Tumor Necrosis Factor-alpha(TNF-alpha), Interleukin 1 alpha and beta (IL-1 alpha & beta) and IL-6.These three pro-inflammatory cytokines are believed to be the “firstresponders” that directly activate TCNs to cause pain and/or itching andare thought to be significant contributors to the development andmaintenance of neuropathic conditions, as well as most skin conditionsthat are associated with inflammation, pain or itching.

Synaptotagmin-1 is a protein present on the surface of vesicles thatcontain and ultimately release neurotransmitters and anti-inflammatoryneuropeptides like substance P from the pre-synaptic endings that bindto the post-synaptic neurons in the DRG and the peripheral TCN endingsin the skin that relay the pain and itch-encoded signals to the brain.Normally, the frequency of the presynaptic neurotransmitter release fromnociceptors are precisely matched so that the intensity, timing andother properties of the original pain or itch signal encoded in thecalcium wave is accurately transmitted to the brain. The delay betweenthe arrival of the calcium wave, neurotransmitter release andpost-synaptic activation is usually about 1/1000^(th) of a second andthe amount released is related to the intensity of the original TCNsignal. This type of neurotransmission is termed “synchronous release,”since the timing of the arrival of the calcium wave is tightlysynchronized to the release of neurotransmitters that triggerpost-synaptic activation of the DRG nerve. Without this precisecoupling, the frequency encoded pain or itch signal becomes distortedand garbled.

When strontium substitutes for calcium, the amplitude of synchronousneurotransmitter release in response to to TCN activation is typicallyreduced by more then 90%. Strontium has an additional signal distortingeffect that significantly distorts the timing of neurotransmitterrelease called “asynchronous release.” In contrast to synchronousrelease that is tightly coupled to the stimulating signal, asynchronousrelease may extend to several hundred milliseconds. With strontium, thetotal amount of neurotransmitter that is released may be the same aswith calcium, however the strength of the synchronous release thatcontains the encoded pain or itch intensity information is stronglyreduced, and the critical timing information is essentially destroyed.This strontium mechanism not only reduces the perceived severity of apain or itch signal, but it also suppresses the release of substance Pat the proximal end of the TCN in the skin at the original site of TCNactivation. Strontium's ability to inhibit the release of TNF-alpha,IL-alpha and IL-6 from keratinocytes is probably due to the samesynaptotagmin-induced release mechanism since it is the secretorymechanism used by virtually every cell. Suppression of synchronousneurotransmitter release also has an important therapeutic benefit forneuropathic pain or pruritus treatment.

Accordingly, in one embodiment, it is therefore desirable to furtheralter the calcium dynamics of nociceptors by further suppressing calciumrelease or by interfering with critical calcium-dependent pathways thatare partially inhibited by strontium.

The Development and Maintenance of Neuropathic Pain or Pruritus RequiresExcessive and Continuous Nociceptor Activation

In order for a neuropathic condition to develop, nociceptors must becontinuously activated by a potent stimulus. The duration of theactivation required may substantially vary depending on the specificnerve injury or stimulant. When such activation occurs, the peripheralnociceptors that innervate the skin and mucous membranes may becomesensitized within hours and may continue to increase their sensitivityto irritants and may even be activated by stimuli that are normally notirritating. Infections such as HIV or Herpes viruses, or chroniccolonization by bacteria such as Staphylococcus aureus that is presentat excessive levels on the skin of atopic dermatitis patients, burnpatients, patients suffering from ionizing radiation or traumatic damageto a nerve are especially potent nociceptor sensitizers. Release ofmultiple inflammatory mediators that accompany any trauma orinflammation are are also important contributors to sensitization.

In order to establish a neuropathic state, sensory nerves in the DRGthat receive sensory input from the TCN must also become sensitized. Asfor the peripheral TCN, the central neurons require sustained, highintensity activation for an extended period of time, that may be asshort as several weeks or much longer. The presence of inflammation,infectious agents, or trauma can accelerate the sensitized, neuropathicstate. Due to neuronal “cross-talk,” it is common for an initially smallpainful portion of sensitized skin, for example, as occurs inpost-herpetic neuralgia, to expand to the adjacent skin via nociceptorsthat were uninjured, including A-delta nociceptors. Sensitizedneuropathic skin may also generate painful stimuli in response tomechanical pressure or temperature changes, a condition known asallodynia.

The sensitized state in both the peripheral nociceptors and theircentral counterparts is a form of activity-dependent plasticity that isvery similar to the neurons in the CNS that form memories. In the caseof neuropathic pain or pruritus, the nociceptive response produces a“memory of pain or itching”. The molecules and pathways that produce thelong-lasting neuronal sensitization are reasonably well defined. Inparticular, the activation of intracellular kinases. Of particularimportance are Protein Kinase A and C (PKA & PKC), each of which existin several different forms—the Mitogen Activated Protein Kinases (MAPK)that include the p38 MAPK, ERK1/2 MAPK and the JNK MAPK. These kinasesare activated by a broad range of environmental “danger signals” andinternal cytokines and growth factors exposures including ionizingradiation, reactive oxygen species (ROS) always accompany infection andtrauma. When activated, these kinases are activated in multiple pathwaysand give rise to sequential cascades that result in regulation andactivation of genes that regulate well over 100 different molecules thatactivate immune cells, produce inflammation and molecules that influenceion channels, and molecular sensors that cause the peripheral andcentral nociceptor sensitization that causes neuropathic pain andpruritus. Among these inflammation and immune-system activating genes,the most important is called Nuclear Factor, Immunoglobulin Light ChainKappa, Enhancer of B Cells, abbreviated NF-Kapa B, called the “MasterRegulator of Inflammation”. Additionally, some of these kinases like PKCcan directly sensitize and activate nociceptors that cause calciuminflux and interfere with strontium's ability to alter the calciumdynamics that occur in neuropathic states.

Accordingly, in one embodiment, it is therefore desirable to combinestrontium with molecules that inhibit one or more of these kinases andregulatory genes that contribute to nociceptor sensitization, activationand generation of neuropathic conditions.

Strontium Binds to a Calcium-Sensing Receptor (CaSR) on Nociceptors thatSuppresses Nociceptor Activation

Most, if not all, cells have a recently-identified surface receptor thatdetects the extracellular calcium concentration. Strontium also bindsand activates the CaSR as efficiently as calcium, but triggersadditional activities. This knowledge resulted in the commercialdevelopment of a simple strontium salt, strontium ranelate, an orallyadministered prescription drug for osteoporosis treatment in over 70countries. Due to strontium's unique ability to mimic calcium's abilityto activate the CaSR and, additionally, to activate additional pathwayslinked to the CaSR, strontium ranelate is the only known osteoporosisdrug that has two independent osteoporosis therapeuticmechanisms—strontium inhibits bone loss by inhibiting bone-resorbingosteoclasts, and simultaneously stimulates osteoblasts that produce newbone.

Nociceptors also have a CaSR that inhibits nociceptor activation whenthe extracellular concentration of calcium is raised above normal, or ifa similar concentration of strontium is administered. This mechanismcontributes to the ability of strontium to rapidly inhibit TCNactivation by, for example, highly acidic chemical peels such as 70%glycolic acid, pH 0.6, that cause burning pain within seconds afterapplication. When strontium is mixed with the acid, burning in andstinging is suppressed by 80% or more so that any remaining sensoryirritation is not bothersome.

Activation of the CaSR also causes activation of several pathways thatare known to increase both acute, chronic and neuropathic pain andpruritus and inflammation. Since in real world use, strontium typicallyinhibits pain and pruritus, it is likely that the pain and itchenhancing effect caused by activation of the CaSR by strontium is, ineffect, negated by other strontium anti-irritant mechanisms. None theless, even a low level, “subclinical’ pain and itch-enhancing effectreduces the ability of strontium to effectively treat, prevent orreverse neuropathic conditions for which any excess TCN activation isknown to promote the neuropathic condition.

Of particular concern is strontium's reported ability to bind to theCaSR and rapidly activate two of the MAPK molecules, p38 and ERK1/2,that are known to be among the primary contributors to peripheral andcentral nociceptor sensitization. Strontium binding to the CaSR is alsoreported to activate an important enzyme, Phospholipase C, that producestwo important regulatory molecules, the aforementioned IP₃, anddiacylglycerol (DAG), both of which contribute to nociceptor activationand sensitization and inflammation. IP₃ is one of the most important andpotent calcium releasing molecules that directly triggers calciumrelease from ER stores. Many of the pain and itch producing chemicalsthat are produced during inflammation, infection or trauma use the IP₃pathway to to activate nociceptors and produce the calcium waves thattransmit pain and itch sensations. DAG is the principle activator ofProtein Kinase C, a family of molecules that directly activatesnociceptors and many of the pathways that produce pain and itch andinflammatory mediators. PKC is also known to be an important nociceptorsensitizer, since PKC inhibition can prevent or reverse neuropathic painin animal models. PKC also activates NF-Kappa B, one of the mostimportant stimulators of molecules that trigger pain, pruritus andinflammation and are thought to be able to directly cause neuropathicsensitization. It should be emphasized that the recognition thatstrontium produces its osteoporosis therapeutic benefits by binding tothe CaSR is very recent and additional strontium-sensitive pathways willlikely be identified. The fact that human nociceptors have the CaSR thatregulate nociceptor activation suggests that the CaSR activation bytopically-applied strontium may be working at a reduced level due tostrontium's ability to inhibit important pain and itch pathways whilesimultaneously activating pathways via the CaSR that are known totrigger pain and itch pathways. Most importantly, since activation ofthese CaSR pathways are known to be important contributors to thedevelopment of neuropathic conditions, strontium's therapeutic potentialmay be substantially compromised.

Accordingly, in one embodiment, it is therefore desirable to createstrontium-based salts, complexes or formulation that have molecularcomponents that specifically inhibit the CaSR pathways known to enhanceneuropathic pain, pruritus and inflammation.

The Primary Goals of the Present Disclosure

It is one object of the present disclosure to inhibit multiplenociceptor pathways by combining strontium with other molecules thatspecifically target pathways that are regulated by strontium and producean overall reduction in pain or pruritus or other benefits to a patient,such as preventing or reversing a neuropathic pain or pruriticcondition. It is another object of the present disclosure to combinestrontium with other molecules that also cause inhibition or stimulationof strontium regulated pathways, but a different steps than thoseregulated by strontium. It is important to note that some nociceptorpathways are inherently inhibitory and if inhibited, the overall resultmay be stimulation of the nociceptor. For this reason, the term“strontium-regulated pathway” will be used to denote the fact that theoverall effect of strontium or the molecules that are to be combinedwith strontium may either stimulate or inhibit a particular nociceptorpathway. It is another object of the present disclosure to combinestrontium and additional molecules in a chemical manner that causesstrontium and the molecules to chemically combine as a “salt” or“complex,” for example a high molecular weight polymer such aspolyanionic polymers such as alginic acid, carrageenan or other polymersthat can form a matrix with strontium and the additionalstrontium-regulating molecules. By creating strontium salts orcomplexes, the osmolarity of a formulation will be reduced in comparisonto having a strontium and two inactive counterions to balancestrontium's two positive charges.

Since it was first described in U.S. Pat. No. 5,716,625 that there is aninherent ability of the strontium ion to selectively suppress stinging,burning pain and itching and associated redness caused by chemicalirritants and by diseases, referred to as its “anti-irritant activity”it was a goal to try to understand how strontium was accomplishing thisactivity with the aim of combining strontium with one or more unrelatedmolecules that amplify the biochemical pathways affected by strontiumand thus produce a more potent therapeutic useful for treating manyserious conditions and diseases for which current treatments havesignificant efficacy or safety limitations and for which strontium wasnot sufficiently potent. The results of this effort revealed anextraordinarily complex combination of strontium-induced regulatoryeffects that were able to predict the observed therapeutic profile ofstrontium. Most importantly, this understanding suggested how to designnew strontium-based compounds, complexes and formulations thateffectively treat pain and pruritus due to nerve damage, conditionsgenerically termed “neuropathic”.

There are many causes of neuropathies, some of which are very common.For example, common neuropathies include viral infection (e.g., HIV, theHerpes varicella zoster virus (VZV) that causes chicken pox and in lateryears, or secondary to immunosuppression, shingles and for many,post-herpetic neuralgia, an intensely painful condition that typicallyoccurs in advanced age.) Diabetes is the most common cause of thetypical burning pain due to glucose-induced nerve damage, serious burns,severe trauma or amputation and a number of drugs, especially some thatare used to treat HIV. While their are oral drugs available likegabapentin (Neurontin™) and pregabalin (Lyrica™) that can providesignificant relief from neuropathic symptoms, they all have potentiallysignificant side effects such as somnolence, dizziness and changes inmentation in more then 25% of patients. Since many neuropathic patientsare in their 70s or 80s and already have health limitations, these sideeffects can be particularly problematic and potentially dangerous. Thisfrequently leads to reduced compliance with the required dosing scheduleand thus reduced patient benefit.

It is a particularly important object of the present disclosure tocreate effective topical drugs, complexes and formulations that aresufficiently safe to be used as needed and without fear of medicallysignifiant side effects, and that can effectively treat pain andpruritus caused by neuropathic conditions. It is also an object of thepresent disclosure to prevent the development of the chronic nervechanges that produce the neuropathic state and to significantly reversethe underlying biochemical changes that produced the neuropathiccondition so that the patient experiences a greatly. reduced level ofpain or pruritus. For some types of neuropathic conditions, the nervechanges and damage may be sufficiently reduced to the point where thepatient is no longer bothered by pain or pruritus.

Accordingly, the complexes and formulations of the present disclosureenhance strontium's ability to treat neuropathic conditons, andgenerally achieve the following goals:

1. Stimuli that Oxidize Intracellular Glutathione Trigger MultipleNociceptor-Activating Pathways

Of the many conditions that may cause nociceptor activation during thedevelopment of neuropathic conditions, the redox state of a nociceptorcan produce some of the most potent acute and chronic nociceptoractivating stimuli that exist. One of the most important regulatorysignals that cause a cell to convert to a defensive state in whichmultiple inflammatory and cell protective immune activators areactivated is the intracellular ratio of reduced to oxidized glutathione.Glutathione is the most plentiful intracellular thiol antioxidant, andis among the most important signal generators that trigger a cell tosynthesize powerful inflammatory mediators and activate genes that, inturn, activate virtually every immune system inflammatory cell. Theratio of reduced glutathione, GSH, to the oxidized form, GSSH, isnormally 9 to 1 or more. When cells are exposed to trauma, infection,inflammation or inflammatory mediators, ionizing radiation or general“cellular stress,” the amount of reduced glutathione plummets anddirectly triggers multiple cascades of gene activation that ultimatelylead to the synthesis of well over 100 inflammatory mediators,pro-inflammatory cytokines (e.g., TNF-alpha, IL-1, IL-6 and manyothers), and cytokines that attract and active inflammatory immunecells, all of which sensitize and activate nociceptors that transmitpain and pruritic signals, and in turn amplify these inflammatorycascades by neurogenic inflammatory pathways. Many of a cells mostimportant regulators of inflammation and immune defense are highlysensitive to a reduction in a cell's GSH concentration, and are directlyactivated by a low GSH/GSSG ratio indicating that a cell is in anoxidative redox state.

Perhaps the most important of these redox-sensitive regulatory pathwaysis NF-Kappa B. This molecule is responsible for that directly orindirectly inducing the synthesis of among the most important andpowerful inflammation activators, including TNF-alpha and many of theinflammatory interleukins and chemokines that attract inflammatory cellsthat secrete mediators that directly activate nociceptors and thusincrease their long-term sensitization and conversion to a neuropathicstate.

Since NF-Kappa B acts as a “final common pathway” for activation ofmultiple inflammatory pathways, substances that reduce or block NF-KappaB activation will have substantial and broad anti-inflammatory activityand will block many forms of immune system-mediated activation ofinflammatory pathways. NF-Kappa B is also one of the many regulatorymolecules that is directly activated by an oxidative intracellularenvironment—one in which the ratio of reduced glutathione (GSH) tooxidized glutathione (GSSG) is minimized. This oxidative evrironmentdirectly activates NF-Kappa B that greatly increases the synthesis ofnociceceptor-activating mediators and cytokines.

Since both peripheral nociceptors with endings in the skin and centralnociceptors in the DRG and spinal cord become sensitized upon continuousactivation, activation of NF-Kappa B is an important and criticalstimulator of neuropathic sensitization.

2. Activation of Toll-Like Receptors by Microbes Activate GeneTranscription by NF-Kappa B That Sensitizes Activate Nociceptors

Keratinocytes constitute about 90% of epidermal cells and have manyreceptors that that can cause nociceptor activation. Among the mostimportant are Toll-Like Receptors (TLRs), molecules that recognizeconserved molecular structures of bacteria, fungi and viruses. Uponactivation, TLRs trigger multiple inflammatory and nociceptor activatingpathways, all of which lead to NF-Kappa B activation.

3. Activation of NF-Kappa B Produces Chemokines that AttractInflammatory Cells

One of the most important consequences of NF-Kappa B is to stimulate theproduction of chemokines, including IL-8, that attract and activateneutrophils, a blood-borne white blood cell (WBC) that typicallyconstitutes over 50% of all WBCs in the blood. Neutrophils are the firstresponders to any type of trauma, infection or inflammatory process andaccumulate at the triggering site in massive quantities. Upon activationby IL-8 and other inflammatory mediators, neutrophils produce massivelevels of powerful oxidants, reactive oxygen species (ROS; e.g.,superoxide, hydrogen peroxide, nitric oxide and hypochlorous acid) thatrapidly deplete GSH from cells, including nociceptors, thus promotingoxidative activation of NF-Kappa B and activation of many kinases,including Protein Kinase A, Protein Kinase C and Mitogen-ActivatedProtein Kinases that act to amplify virtually all inflammatory pathwaysthat directly activate nociceptors.

Activation of these multiple independent inflammatory pathways andinflammatory cells result in intense activation of nociceptors thatcontribute to the development of neuropathic sensitization andneuropathic pain and pruritus.

Such activation of nociceptors also causes them to release Substance Pthat directly triggers mast cell activation and release of histamine,TNF-alpha, IL-1, IL-6, IL-8 and many more inflammatory substances thatfurther activate nociceptors. Due to the simultaneous activation ofmultiple inflammatory and nociceptor-activating pathways, there is a netamplification of nociceptor activation that is known to directly lead noneuropathic pain and pruritus.

4. Complexes of Strontium, and the Two Counterions, Cysteine-BasedAnti-Oxidants and Polyhydroxyphenols, Block Nociceptor Activation byBlocking Multiple Inflammatory Pathways at Multiple Independent Steps ina Synergistic Fashion

As described previously, by interfering with intracellular calciumdynamics within nociceptors, strontium in effect garbles the normalcalcium-encoded signals that contain the pain and pruritic signals thatultimately produce the conscious appreciation of pain and pruritus.Strontium also binds to many critical calcium-dependent pathways thatnormally activate nociceptor pathways, including inflammation-triggeringkinases that lead to NF-Kappa B activation and continued nociceptoractivation.

The two counterions act at different steps in the same inflammatorypathways inhibited by strontium, and thus in effect amplify the basicanti-irritant activity and nociceptor-protective activities ofstrontium. Examples of the key strontium-amplifying activities of thesetwo specific counterions are discussed below:

A. Cysteine-Based Anti-Oxidants Inhibit Multiple Strontium-RegulatedInflammatory Pathways that Activate Nociceptors

Upon topical application of a cysteine-based anti-oxidant to the skin,the acetyl group of the cysteine-based anti-oxidant is rapidly removedleaving free cysteine Cysteine is the rate-limiting amino acid thatcontrols the synthesis of reduced glutathione (GSH). Accordingly,administration of a cysteine-based anti-oxidant to skin rapidlyincreases the concentration of GSH and reduces the intracellularconcentration of oxidized glutathione (GSSG), thus normalizing anociceptor's redox state. This has the immediate effect of inhibitingthe activation of NK-Kappa B and the activation of many otherredox-sensitive inflammatory pathways, thus reducing nociceptoractivation by both direct and indirect pathways. Cysteine-basedanti-oxidants also have a unique anti-oxidant activity due to theirthiol (SH groups) that suppress the ability of nitric oxide tocovalently bond to and activate inflammatory kinases that are known todirectly contribute to neuropathic conditions. Cysteine-basedanti-oxidants also directly inactivate other oxidants that activateinflammatory pathways and, most importantly, they inhibit nociceptoractivation. By combining a cysteine-based anti-oxidant with strontium,one of the most important regulatory controls of nociceptor activationis reduced by shifting the nociceptor's redox state to a high GSH/GSSGratio.

Due to its thiol group, cysteine-based anti-oxidants also have theability to directly bind to the thiol groups of cysteine residues withinmolecules that are part of inflammatory pathways that contribute tonociceptor activation. Since there are many thiol-sensitive regulatorymolecules, cysteine-based anti-oxidants have the ability to blockoxidation of critical cysteines in such molecules and thus blockactivation that leads to increased inflammation and nociceptoractivation. For many redox sensitive cysteine regulated pathways, theconcentration of calcium within nociceptors is increased and, as formany other nociceptor activators, the resultant calcium-concentrationencoded pain, pruritus and activation signals contribute to theformation and the long-term continuation of neuropathic conditions. Byblocking such cysteine oxidation induced calcium release, cysteine-basedanti-oxidants contribute to strontium's inherent ability to similarlyinhibit calcium-encoded signals, but by non-strontium mechanisms. Byblocking calcium-dependent signals with distinct mechanisms, the overallnociceptor inhibitory activity is increased.

B. Polyhydroxyphenols Inhibit Multiple Strontium-Regulated InflammatoryPathways that Activate Nociceptors

Like the cysteine-based anti-oxidant, the polyhydroxyhenols are powerfulanti-oxidants. The polyhydroxyphenols, however, possess several uniqueanti-oxidant mechanisms not possessed by the cysteine-basedanti-oxidant. The polyhydroxyphenols act to inhibit multipleoxidant-generating pathways that are only indirectly affected bycysteine-based anti-oxidants. By combining multiple, independentanti-oxidant inhibitory mechanisms, the counterions in combination actwith a maximum anti-potency to inhibit redox sensitive activation ofNF-Kappa B and many other nociceptor activation pathways that aretriggered by exposure to oxidants.

An exemplary polyhydroxyphenol in the practice of the present disclosureis gallic acid (3,4,5-trihydroxybenzoic acid). Gallic acid (GA), andsimilarly structured polyhydroxyphenols, have multipleanti-inflammatory, anti-oxidant and inflammatory cell inhibitoryactivities that amplify the strontium regulated pathways that lead tosuppression of nociceptor activation.

The polyhydroxyphenolic structure of gallic acid, caffeic acid,quercetin, luteolin, myricetin and similar polyhydroxyphenolicanti-oxidants provide such molecules with a number of importantproperties that both inhibit nociceptor-activating pathways suppressedby strontium and provide specific abilities to bind to and suppressseveral important kinases that are known to be important for developmentof neuropathic pain and pruritus conditions.

These molecules all have hydroxyl groups that are, in one embodiment,adjacent to each other on the phenolic moiety in meta and para positionsand mimic the three dimensional structure of adenosine triphosphate(ATP), a molecule that must bind to the active sites of kinases likeprotein kinase C and other regulator kinases that are part of signaltransduction pathways that active multiple inflammatory pathways,activate NF-Kappa B and directly activate nociceptors. These kinases arealso known to be necessary for development of neuropathic nociceptorsensitization and neuropathic pain and pruritus.

Polyhydroxyphenols also directly bind to components of NF-Kappa B andcause a direct inhibition of activation. The ability of the counterionsto inhibit NF-Kappa B activation by multiple independent mechanismsproduce an inhibitory effect greater than inhibition by only onemechanism.

The polyhydroxyphenols also inhibit the expression of multiple cellularadhesion molecules like ICAM-1, VCAM-1 and members of the selectinadhesion molecules that enable neutrophils and monocytes to extravasatefrom blood vessels and accumulate at sites of inflammation, thuscontributing to nociceptor activation.

Polyhydroxyphenols also have multiple anti-oxidant activities that havemechanisms distinct from those of the cysteine-based anti-oxidants. Forexample, gallic acid and the other polyhydroxyphenols directlyinactivate supereoxide, hydrogen peroxide, hydroxyl radicals andhypochlorous acid, thus preventing them from shifting the intracellularGSH concentration from being reduced, which activates NF-Kappa B andother redox activated inflammatory regulatory molecules and moleculesthat directly activate nociceptors.

The polyhydroxyphenols also posses a unique ability to inhibit theFenton Reaction by which low concentrations of ferrous iron (Fe₂ ⁺⁺) andcopper (Cu⁺⁺) catalytically produce the highly toxic and inflammatoryhydroxyl radical that is a powerful inflammation activator.

In one embodiment, the polyhydroxyphenol is selected from the groupconsisting of: gallic acid, quercetin, caffeic acid, myricetin, andleutolin. Such molecules have powerful inhibitory activities on one ofthe most important inflammatory molecules present in the skin, the mastcell. Mast cells are present in the dermis and submucosal tissuesthroughout the body and are among the most important sources ofpreformed inflammatory mediators like histamine, TNF-alpha, IL-1, IL-6.

IL-8 and over 20 other chemokines and inflammatory mediators, all ofwhich directly or indirectly activate nociceptors. Nociceptor activationis also a major stimulator of Substance P release from Type CNociceptors that directly activate mast cells, neutrophils and everyother type of inflammatory white blood cell. The combined ability ofstrontium to inhibit nociceptor activation, Substance P release andpolyhydroxyphenolic inhibition of mast cell activation provides apowerful additive synergistic inhibitory activity on inflammation andnociceptor activation.

Both cysteine-based anti-oxidants and polyhydroxyphenols additionallyare powerful inhibitors of prostaglandins and leukotrienes, particularlyPGE₂ and LTB₄. PGE₂ is one of the most important nociceptor sensitizersthat is synthesized in virtually all inflammatory conditions. LTB₄ isone of the most important attractants and activators of neutrophils thatare the first cell to accumulate in large numbers at sites of trauma,irritation, infection and inflammation and are among the most importanttriggers of nociceptor activation. Each class of counterion inhibitsprostaglandin and leukotriene synthesis by different mechanisms.

Both counterions also have a critical ability to inhibit severalinflammatory and nociceptor activating pathaways that are stimulated bystrontium, thus potentially enhancing strontium's ability to inhibitacute and chronic pain and pruritus and to inhibit nociceptorsensitization that is known to be important for development ofneuropathic conditions.

In particular, strontium's ability to activate the Calcium-SensitiveReceptor (CaSR) on cells, including nociceptors is known to activateProtein Kinase A, Protein Kinase C and NF-Kappa B. Activation of each ofthese molecules is known to contribute to nociceptor activation andneuropathy development. The counterions limit such activation. Indeed,the combination of the cysteine-based anti-oxidant polyhydroxyphenolsinhibit the activation of each of these strontium activated molecules bymultiple independent mechanisms, thus negating the undesirableactivities of strontium that otherwise limits it's overall anti-irritantactivity and ability to inhibit the development and maintenance ofneuropathic conditions.

By combining strontium with the counterions described herein, theresultant complexes are more efficient inhibitors of many of the samenociceptor-activating pathways that are inhibited by strontium bymultiple, overlapping and distinct mechanisms. Finally, the combinationthese strontium amplifying molecules also inhibit strontium-activatedpathways that contribute to pain, pruritus and development ofneuropathic diseases.

Also contemplated is a composition that incorporates a combination ofstrontium with a mixture of polyhydroxyphenols. Using more than onepolyhydroxyphenol has a synergistic effect due to the differentialactivities of each polyhydroxyphenol. It is contemplated that thissynergistic effect has enhanced efficacy in treating sensory irritationthat includes but is not limited to pain, pruritus, and development ofneuropathic diseases. In one embodiment, the mixture includesmonophenolic and polyphenolic polyhydroxyphenols. In one embodiment, themixture includes monophenolic and biphenolic polyhydroxyphenols. Inanother embodiment, the mixture includes monophenolic and triphenolicpolyhydroxyphenols. In another embodiment, the mixture includesbiphenolic and triphenolic polyhydroxyphenols. In another embodiment,the mixture includes monophenolic, biphenolic, and triphenolicpolyhydroxyphenols. In another embodiment, the mixture includes an ATPanalogue with a monophenolic, biphenolic, or triphenolicpolyhydroxyphenol. In yet another embodiment the mixture ofpolyhydroxyphenols is gallic acid and caffeic acid. In anotherembodiment, the mixture of polyhydroxyphenols is myricetin and caffeicacid. In another embodiment, the mixture of polyhydroxyphenols ismyricetin and gallic acid. In another embodiment, the mixture ofpolyhydroxyphenols is myricetin, gallic acid, and caffeic acid.

The Complexes of the Present Disclosure

The compositions and formulas of the present disclosure have two generaldesign & therapeutic goals: (1) Reduce the Negative Effects of Strontiumon Neuropathic Treatment; and (2) Increase Strontium's BeneficialActivities for Neuropathy Treatment.

After strontium was first commercialized, it became clear that whilestrontium was safe and effective in many commercial applications, itsuffered from a number of deficiencies that ultimately limited itspotential therapeutic utility. For example, strontium at a concentrationof 2-6% in a formulation frequently caused transient stinging if thetreated skin was broken or had a damaged ‘barrier’ due to trauma,chemical exposure, infection or disease. Patients with ‘diaper rash’,both infants and people who are incontinent usually experienced intensepain described as stinging for 5-10 seconds when using a 4 or 6%strontium formulation. While not harmful, it was not tolerable for manyinfants. Similarly, strontium at higher concentrations was not beapplied to thermal burns, cuts or skin that had been highly excoriateddue to scratching. Attempts to develop emulsion-based lotions or creamswere limited by the inherent emulsion destabilizing effect ofelectrolytes like strontium and its counter ions that disrupt the veryelectrostatic forces that create emulsions.

In one embodiment, the compositions of the present disclosure aretripartite complexes containing at least three components, of which, onecomponent is strontium. In another embodiment, the compositions of thepresent disclosure are bipartite complexes containing at least twocomponents, of which, one component is strontium. The components of thetripartite and bipartite complexes are discussed below.

A. Strontium

Strontium is present as a divalent cation. Strontium is designated byits commonly used atomic symbol, ‘Sr’ and is depicted below.

Strontium mimics the ability of calcium to pass through voltagedependent calcium channels. As such, it may compete with Ca++ forbinding to some receptors. Calcium is thought to play a role in the painprocess by regulating the release of neurotransmitters, and thusstrontium's analgesic effect may be in preventing calcium's binding tonerve cells.

Strontium is available as an inorganic or organic salt which is watersoluble at room temperature in the range of 1 to 100 g/l. Inorganicsalts include, for example, strontium chloride, strontium sulfate,strontium carbonate, strontium nitrate, strontium hydroxide, strontiumhydrosulfide, strontium oxide, strontium acetate, etc. Organic saltsinclude, for example, negatively charged organic acid such as a mono-,di-, tri- or quatro-carboxylic acid, or an amino carboxylic acid thatmay have a linear or branched carbon chain of from 2 to 30 carbon atomsand one or more amino groups attached thereto. The amino carboxylic acidmay be a natural or synthetic amino acid. Examples of organic strontiumsalts include, for example strontium glutamate, strontium aspartate,strontium malonate, strontium maleate, strontium citrate, strontiumthreonate, strontium lactate, strontium pyruvate, strontium ascorbate,strontium alpha-ketoglutarate or strontium succinate. Other examples ofstrontium salts, and methods for preparation thereof, can be found, forexample, in US Published Application No. 2010/0048697.

In the form of an organic salt, it should be understood that thecounterion cannot have a higher affinity for strontium than theanti-oxidants and/or polyhydroxyphenols described herein for formingstrontium complexes.

B. Polyhydroxyphenols

Polyhydroxyphenols are phenolic compounds possessing at least twohydroxyl groups, preferably in the ortho and para positions. Oneexemplary compound is 3,4,5-trihydroxy benzoic acid, also called gallicacid. The term “polyhydroxyphenol” does not include carboxylic acids,such as ranelate.

The polyhydroxyphenol can be added to the compositions described hereinin essentially purified form, or they can be added in the form ofpolyhydroxyphenol-containing plant extracts, such as green tea and soyextracts.

The flavonoids are polyphenolic compounds possessing 15 carbon atoms;two six-carbon benzyl rings that are usually joined together, by alinear, saturated three carbon chain. Other flavinoids may consist oftwo benzyl rings joined together by a third 5- or 6-carbon ringstructure. Flavinoids constitute one of the most characteristic classesof compounds in higher plants. Many flavinoids are easily recognized asthe pigments in flowering plants.

The polyhydroxyphenol may also function as an anti-oxidant. For example,gallic acid is a tri-hydroxyphenolic structure that has anti-oxidantactivity. The monomeric phenolic compounds include for example, gallicacid (3,4,5-trihydroxybenzoic acid) and caffeic acid. Both compoundshave a carboxylic acid group, which may be esterfied with a sugar moietysuch as glucose. In the case of gallic acid, such esterfication producesglucogallin. Other organic esters may also be effective, such as theethyl ester of gallic acid, ethyl gallate, or the propyl ester of gallicacid, propyl gallate.

Also contemplated by the present disclosure are polymeric phenoliccompounds that have two or more aromatic rings that typically, but donot necessarily have the same structure. One such example isreservatrol. Aother is pentagalloyl glucose, which consists of fivegallic acid residues that are esterfied to one glucose molecule. Thismolecule will be cleaved in vivo by non-specific esterases, which freethe individual gallic acid residues. The use of such forms ofpolyhydroxyphenolic compounds has the added advantage of loweringosmotic activity, since one molecule of pentagalloyl glucose producesone unit of osmotic activity, as compared to five units of osmoticactivity produced by the use of five separate molecules of gallic acid.

Tannic acid is another example of a high molecular weight gallic acidpolymer in which one or more esterfied gallic acid residues areesterfied to a central glucose molecule.

Ellagic acid is an example of a gallic acid dimmer. While this moleculeno longer possesses the gallic acid-like phenolic structure, it doesmaintain many of the same bioactivities of gallic acid and is thususeful in the practice of the present disclosure.

Compounds having a flavone backbone include, for example, quercetin, andepicatechin (EC) and derivatives thereof, such as epigallocatechingallate (EGCG found in green tea), epigallocatechin (EGC) andepicatechin gallate (ECG).

Other polyhydroxyphenolic compounds include, for example, myricetin,luteolin, naringen, genistein and nordihydroguaiaretic acid (NDGA).

In one particular embodiment, the polyhydroxyphenols that are usefulalso exhibit one or more carboxyl groups, such as gallic acid andcaffeic acid. The carboxyl group can serve as an additional counterion,and also assist in matrix formation with an optional polyanionicpolymer.

In another embodiment, the polyhydroxyphenols that are useful in thepractice of the present disclosure are inhibitors of Protein Kinase C(PKC) isozymes, and in particular, PKC epsilon. This is particularlytrue of strontium-polyhydroxyphenol complexes, since the strontium canmimic the effects of calcium as a cofactor for PKC. For example,luteolin and quercitin are known to inhibit PKC isozymes. See, forexample, Cancer Res. 70 (6): 2415-2423 (2010); and Biochem. Pharmacol.38: 1627-1634 (1989). Also as described in demonstrated by both of thesearticles, methods for determining the degree of inhibition of PKC bycompounds are known in the pharmaceutical arts. As used herein, thepolyhydroxyphenol will be considered to be a PKC inhibitor if itsuppresses 10% or more of the activity of the PKC.

In yet another embodiment, the polyhydroxyphenols and theircorresponding strontium complexes are known inhibitors of calmodulin.More particularly, they inhibit calmodulin-promoted phosphodiesteraseactivity. See, for example, Plant and Cell Physiol. 26(1) 201-209(1985), which describes inhibition of calmodulin-promotedphosphodiesterase activity by flavonoids such as catechin, epicatechin,quercetin, caffeic acid and naringenin. As used herein thepolyhydroxyphenol will be considered to be a calmodulin inhibitor if itsuppresses 10% or more of the activity of calmodulin.

In still another embodiment, the polyhydroxyphenols and theircorresponding strontium complexes are known NIP analogues. This is themechanism by which they inhibit protein kinases in that they competewith ATP for the protein kinase ATP binding site, which prevents proteinkinase from being active. Studies of the activities of various ATPanalogues, such as flavonoids, are known in the literature. See, forexample, Phytochemistry Reviews 1:325-332 (2002), wherein the effect offlavonols on ATP-dependent activities was studies.

C. Cysteine-Based Compound

Cysteine is abbreviated by the three letter amino acid code, Cys. Inchemistry, a thiol group contains sulfur that is covalently bound to twogroups, (1) a carbon, designated ‘C’, or if the carbon is part of alonger chain of carbon atoms, the letter ‘R’ is frequently used todesignate this carbon chain. (2) Attached to the carbon atom by acovalent bond is the second part of a thiol group, a hydrogen atom,designated by its atomic symbol, ‘H’. The intact thiol group is thusdesignated ‘—SH’ in which the SH group is bound to a carbon, and iscommonly designated ‘—C—SH’, or if the —SH thiol group is attached to achain of carbon atoms, R—SH is the commonly used representation. Thiolsare also referred to as mercaptans in reference to their ability to bindstrongly to the element mercury—thus the Latin term ‘mercurium captans’that literally means ‘capturing mercury’.

The term “cysteine-based compound” includes cysteine and cystine.Alternatively the cysteine-based compound is acetylated at the aminogroup of the cysteine to produce N-acetyl-cysteine, commonly abbreviatedacetylcysteine or NAC. Cysteine exists in two enantiomeric forms,designated ‘L-cysteine’ and ‘D-cysteine’, of which the L form is used inliving organisms while the D form is not. While both the L and D formsare contemplated in the present disclosure, the L form of acetylcysteineis most preferred, i.e., NAC. If the D form of NAC is intended, it willbe referred to as D-NAC. In addition, both L-Cys and D-Cys can formdisulfide bonds between the two thiol groups to form a ‘dimer’,literally a pair of Cys molecules. Such disulfide bonds occur in manyproteins and play a critical regulatory role in biochemical pathways dueto the ease of their reversible formation by oxidative processes anddissolution by reductive processes. By convention, a disulfide-bondeddimer of cysteine is termed cystine. Thus one cysteine molecule underappropriate reducing conditions or enzymatic processing will yield twocysteine molecules. Cystine can be formed from either two L-Cysmolecules, two D-Cys molecules, or one L-Cys and one D-Cys molecules.Another exemplary cysteine-based compound is N,S-diacetylcysteine. Allof such variants are incorporated within the present disclosure.

D. Aromatic Amino Acids

Aromatic amino acids have an aromatic ring in their side chain. Thearomatic amino acids are phenylalanine, tyrosine, tryptophan andhistidine. All amino acids, except glycine, have two isomers which arechiral and are referred to as “D” and “L.” The L form is the predominantform in living organisms and is the form used to build proteins. Whileboth D and L forms of the aromatic amino acids are contemplated in thepresent disclosure, the L form is preferred.

Aromatic amino acids act as agents that increase the receptor responseto strontium and calcium. The site which the aromatic amino acid bindsdiffers from the strontium and calcium binding site.

E. Cleavable Bonds

In one embodiment, the complexes of the present disclosure utilize acleavable bond to join the polyhydroxyphenol and the cysteine-basedcompound together in the tripartite complexes. Complexes which use acleavable bond to join the polyhydroxyphenol and cysteine-based compoundtogether in the tripartite complexes will be referred to as the“conjugated” form of the compounds.

As defined above, a cleavable bond is a chemical bond joining twomolecules together that can later be broken, thus releasing the twomolecules from each other. The present disclosure contemplates usingcleavable bonds that are known in the art, examples of which include,but are not limited to peptide bonds, thioesters bonds, enzymaticallycleavable bonds, disulfide bonds, pH dependent bonds, and other covalentbonds.

The use of cleavable bonds in the present disclosure may create a lessactive form of the compound that can be converted to an active form. Thebenefits of using an less active form are known in the art. For example,the less active form may be used to enhance the stability of a compoundallowing for an increase the shelf-life or a greater range of storagetemperatures. The less active form may also be used to ensure that thecompound reaches it target destination before becoming active.

The use of cleavable bonds in the present disclosure offer otheradvantages that may improve the performance of the complex. For example,the conjugated form may be used to reduce the osmolarity of a chemicalcompound, which in the present disclosure is useful since the human bodyhas molecular sensors that recognize changes in osmolarity and triggerpain and itch pathways. The conjugated form may also be used to changethe solubility of a compound, for example, making the compound morelipophilic to allow better uptake into cells.

As described elsewhere herein, limiting the osmolarity of the presentcomposition herein may be beneficial. Accordingly, conjugatingpolyhydroxyphenol to the cysteine-based antioxidant lowers theosmolarity by approximately one third, thus enhancing efficacy. Theaddition of a neutral or anionic polymer reduces the osmolarity evenfurther by allowing multiple tripartite complexes to attach to onepolymer.

In one embodiment, the cleavable bond of the conjugated form of thecompound is cleaved upon application of the compound to the skin. Oneexample of this embodiment is the use of thioester to join gallic acidto NAC. When this compound is applied to human skin, non-specificesterases on the surface of the skin cells cleave the thioester bond.

In another embodiment, only a small percentage of the cleavable bonds ofthe conjugated form of the compound are cleaved upon application of thecompound to the skin or thereafter, the majority of the conjugated formof the compound is taken into the cell where the cleavable bonds arecleaved. The uptake of the conjugated form of the compound allows for agreater concentration of strontium to be present within a cell thanapplying a strontium salt to the skin or orally ingesting strontium.

In another embodiment, the cleavable bond is cleaved upon application ofa second compound containing a cleaving agent. A cleaving agent is anagent that cleaves specific chemical bonds. The second compound can beapplied to the skin immediately after the application of the conjugatedform of the compound or alternatively, the two compounds can be mixedtogether immediately before application to the skin. Examples ofcleaving agents include, but are not limited to enzymes, reducingagents, oxidizing agents, light, and chemicals that induce pH changes.

In one embodiment, the complexes of the present disclosure include: 1)one atom of strontium; 2) one molecule of gallic acid; 3) one moleculeof N-Acetyl-L-Cysteine, (NAC). In another embodiment, the gallic acidand NAC are joined by a thioester and complexed with gallic acid.

Optional Ingredients 1. Optional Neutral or Ionic Polymers A.Hyperosmotic Formulation Instability of Strontium Formulations

Strontium's anti-irritant activity is due to the divalent strontium ion.Due to it's dual positive charges, anionic counterions are required tobalance the electrostatic charge and thereby create a strontium salt.Among many possible strontium salts, preferred salts included strontiumnitrate and strontium chloride, either as the hexahydrate or in ananhydrous salt form. In both of these salts, the negatively-chargedcounterions, Nitrate (NO₃ ⁻) or Chloride (Cl⁻) contribute to the ionicstrength and osmolarity of the formulation, but not to the overallanti-irritant benefits. Since many formulations such as lotions, creamsand hydrogels rely on a delicate balance of factors that produce stableemulsions or hydrogels, formulations with high ionic strengths commonlyprevent stable emulsion formation. For example, emulsions in which morethan about 6-7% strontium nitrate or strontium chloride hexahydrate,(equivalent to about 2% elemental strontium) are incorporated tend to beunstable and separate. Similarly, hydrogels containing more than about12% to 13% (equivalent to about 4% elemental strontium) of these saltsalso tends to be unstable. Clinical studies have shown that higherstrontium concentrations produce increased clinical benefits.Consequently, it is medically and commercially advantageous to createcommercially acceptable and stable formulations with high strontiumconcentrations. Since two thirds of the strontium nitrate or chloridesalt represents ions that act to destabilize formulations, it isimpossible to achieve this goal using available ingredients.

B. Hyperosmotic Formulations Can Also Physically Damage Tissues andCause Pain

Topical formulations with high osmotic activity (over 400 mOsm, such asbetween 400 and 2000 mOsm) may also damage delicate tissues and maycause pain, especially in non-keratinized skin that have a mucousmembrane or that has a damaged ‘barrier function’ due to physicaltrauma, infection or inflammation. Such hyperosmotic-induced damage ispopularly known as ‘. . . the salt in the wound effect . . . ’ and itoccurs when osmotic forces cause water to flow out of the cells andtissues into the hyperosmotic formulations. Recent scientific reportsalso demonstrate that application of hyperosmotic formulations candirectly activate certain molecules that act as osmolarity sensors and,when activated, activate pain sensing nerves and immune and non-immunecells that can produce inflammation and cellular damage. This recentunderstanding has potentially critical importance for the goal ofpreventing the development of chronic or neuropathic pain.

The potential importance of this observation has critical importance forthe treatment of or the prevention of neuropathic pain development sincechronic nociceptor activation is known to be required for painfulneuropathic conditions to develop. The recent discovery that there aremultiple ion channels and related hyperosmotic molecular sensors thattrigger nociceptor activation upon exposure to hyperosmotic topicalformulations suggests that their chronic use may predispose thedevelopment of neuropathic pain conditions if there is coexistingchronic or severe damage to nociceptors. In this scenario, long-termapplication of a hyperosmotic formulation to skin, and especially todelicate mucous membranes of, for example, the vaginal or cervicalmucosa my cause low level, but long-term activation of nociceptors, thuscontributing to their sensitization. It is believed that progression offrom an acute, transient pain state to a chronic, long-lasting,‘neuropathic state’ is due to continued excessive nociceptor activationthat results in increased expression of genes that reduce the magnitudeof an irritant stimuli, also called the irritant or nociceptoractivation ‘threshold’ and thus cause increased nociceptor activationand an increased perception of pain and/or pruritus. Additionally, thesegenes can also increase the synthesis of inflammation-producingmolecules that further irritate the nociceptors, thus producing what iscommonly termed ‘a vicious spiral’ of increasing sensory irritation andinflammation.

C. Hyperosmotic Formulations Can Also Increase Infection by Herpes & HIV

In addition to causing painful or pruritic sensations and inflammation,even low-level, but chronic exposure to nociceptor-activating irritantscan predispose to infection by a multitude of pathogenic microbes ofwhich Herpes simplex viruses 1 and 2 (HSV) and the HumanImmunodeficiency Virus (HIV) cause the greatest threat to public health.While a detailed explanation of the many and varied reasons for whynociceptor activation and coexisting inflammation facilitates infectionby HSV and HIV is not discussed in detail herein, in essence, therelease by Type C Nociceptors of inflammatory neuropeptides likesubstance P is known to damage the anatomical ‘barriers’ of bothkeratinized skin and mucosal membranes that block viral infection. Theresultant inflammation is also known to activate inflammatory immunecells that, ironically, contribute to the ability of both HSV and HIV tocause acute infection and in the case of HSV, reactivation of anexisting latent infection.

Application of hyperosmotic topical formulations of, for example,lubricants or microbicides, to the mucous membranes of male or femalegenitals or to the vaginal, cervical or anal tissues may greatlyincrease the possibility of transferring one of these viruses or otherpathogenic microbes that cause sexually-transmitted diseases from aninfected person to an otherwise healthy person. It is therefore beadvantageous to create strontium-containing formulations with highstrontium concentrations that are designed to minimize the osmolarity ofthe formulation. It is one object of the present disclosure that isinherent in it's molecular design to provide a strontium-containingmolecule having a minimal osmotic activity and that possesses multipletherapeutic components that maximize the amount of therapeuticallybeneficial strontium that can be applied.

In one embodiment, the compositions of the present disclosure include astrontium complex and a polymer capable of ionic association with thecomplex, in which case the complex and the polymer form a matrix. Suchmatrix formation enhances the bioavailability of the complexes andtherefore prolongs the therapeutic effect of such complexes. Inparticular, when the strontium complex includes a polyhydroxyphenol,such compounds have a high affinity for polymers, such aspolyvinylpyrrolidone (PVP).

For example, PVP is commonly used as an inert carrier of therapeuticallyactive molecules. Due to the varying polar structure of the PVP polymer,it presents multiple, repeating sites to which atoms and molecules maybind via ionic forces. Upon subsequent exposure to ionic media, such aswater, the bound substance may be released into the media over anextended period of time. Thus facilitating gradual release of thesubstance as a function of pH and other adjustable conditions, such astemperature, etc. As such, the PVP acts as a “molecular reservoir”providing for sustained release of therapeutic substances.

The PVP polymer may be in its native form, or it may be chemicallymodified by derivatization and/or crosslinking to adjust the “releasing”properties of the polymer.

The polyhydroxylated phenols, such as gallic acid, have a high affinityfor PVP. As such, the combination of PVP, gallic acid and divalentcationic strontium forms a complex ionic matrix that facilitatescontrolled release of the strontium after administration.

Such polymer-based compositions also minimize osmolarity which can leadto unstable formulations and physically damage tissues and cause pain.For example, topical formulations with high osmotic activity may damagedelicate tissues, especially in non-keratinized skin that has a mucousmembrane or a damaged “barrier function” due to physical trauma,infection or inflammation.

Neutral or anionic polymers include, for example, polyvinylpyrrolidone(PVP), cyclodextrins, carragenans, alginic acid, xanthan gum, sulfatedpolysaccharides such as carrageenan, dextran sulfate, pentosanpolysulfate, condroitin sulfate, heparin sulfate, etc.

Matrices formed between monomeric compounds such as flavonoids andpolymers such as cyclodextrin are known in the art. See, for example,PLoS ONE 6 (4): e18033(2011).

Formulation and Administration

There are two principle physical methods by which the elements that makeup the complexes of the present disclosure can be administered to apatient.

Method 1: In the first method, the strontium, and the counterions, acysteine-based anti-oxidant, polyhydroxyphenol, or an aromatic aminoacid form a single complex in which each the three atomic and molecularelements are held together by ionic chemical bonds. Such bonds areformed due to the two positive charges of the strontium cation and dueto the negative charges present on the counterions that occur atphysiological pH and lower. The three ionically bonded molecules form a“salt.”

In one embodiment, the salt is formed by combining strontium with acysteine-based anti-oxidant and a polyhydroxyphenol. In anotherembodiment, the salt is formed by combining strontium and twopolyhydroxyphenols. In yet another embodiment, the salt if formed bycombining strontium and two aromatic amino acids.

In one embodiment, the tripartate nature of the complexes of the presentdisclosure is represented by gallic acid having a negative charge, thedivalent strontium atom possessing two positive charges, andN-Acetyl-L-Cysteine (Acetylcysteine, NAC) with it's negatively chargedcarboxyl group. Due to the single negative electrostatic fields thatsurround the negatively charged carboxyl groups of both gallic acid andNAC, and due to their attraction to the two positive charges of thesingle strontium ion, these three substituents form a “salt”.

In one embodiment, the counterions, a cysteine-based anti-oxidant and apolyhydroxyphenol, are conjugated together with a cleavable bond. Theconjugated counterions are then combined with the strontium. Thecleavable bond may be any type of cleavable bond known in the art thatdoes not interfere with the ionic chemical bonds that will form betweenthe strontium cation and the counterions. One non-limiting example isjoining gallic acid and NAC together with a thioester bond.

Method 2: The second method by which a complex of the present disclosurecan be formulated and therapeutically administered to an animal or humansubject is by the incorporation of the separate substituents in apharmaceutically-acceptable vehicle or delivery system. For tripartitecomplexes, one atom of strontium, one molecule of a cysteine basedanti-oxidant and one molecule of a polyhydroxyphenol are all added to apharmaceutically-acceptable vehicle. For bipartite complexes, one atomof strontium and two molecules of polyhydroxyphenol are all added to apharmaceutically-acceptable vehicle. Alternatively, for bipartitecomplexes, one atom of strontium and two molecules of aromatic aminoacids are all added to a pharmaceutically-acceptable vehicle. This typeof relationship in which a single atom or molecule is combined withother atoms or molecules on a one-to-one basis, that is in which aninteger number of atoms or molecules are combined is referred to as onthe basis of their molar relationships. In the example of the tripartitecomplex described above, the molar ratio of each substituent is 1:1:1,that indicates 1 atom of strontium+1 molecule of gallic acid+1 moleculeof NAC. In the example of the bipartite complex, the molar ration ofeach substituent is 1:2, that indicates 1 atom of strontium+2 moleculesof polyhydroxyphenol or aromatic amino acid.

In another embodiment, the pharmaceutically-acceptable vehicle to whichthe bipartite are tripartite complexes are added also contains apolymer. Due to the nature of the polymer, the ratio of strontium tocounterion does not need to be one molecule of strontium to twomolecules of counterions. The polymer itself provides multiplecounterions to which the strontium ionically binds.

For certain therapeutic applications, it may be desirable to substitutea ‘D’ version of cysteine for L-cysteine that occurs within livingorganisms. For example, since L-Cys is used as a substrate for thesynthesis of the tripeptide, glutathione, gamma-Glu-Cys-Gly, where Gluis the common three letter amino acid code for glutamic acid and Gly isthe code glycine. Since the amount of cysteine that is available to acell is the principle rate-limiting factor that determines how muchglutathione is produced by a cell, increasing or decreasing the amountof cysteine can regulate intracellular glutathione synthesis. When NACis administered to cells, either topically or systemically, the acetylgroup is rapidly removed within a cell and the cysteine is used tocreate new glutathione.

Glutathione is known to be the most abundant and important intracellularthiol anti-oxidant present in all cells, and since the amount ofglutathione in cells is known to be a powerful regulator of cellularactivity, function and activation of genes that produce powerfulinflammatory molecules, including pro-inflammatory cytokines. For thisreason, it may be therapeutically advantageous for certain conditions ordiseases to deliver one strontium atom in combination with twoL-Cysteine molecules, or one strontium atom in combination with oneL-Cystine molecule, that will be reduced to two L-cysteine moleculeswithin cells) that will result in the maximum synthesis of glutathionewithin cells.

For treating other conditions or diseases, it may be advantageous todeliver an intermediate amount of L-cysteine for conversion intoglutathione. Since D-cysteine is not used to create glutathione, but itdoes retain its direct anti-oxidant activity due to its thiol (-SH)group, it is certainly useful in the practice of the present disclosure,wherein the D-Cys delivers a maximum level of direct thiol-relatedanti-oxidant activity while delivering only an intermediate level of newglutathione synthesis.

The present disclosure contemplates the use of such variants of thecomplexes since a particular variant may have therapeutic advantageswhen treating certain types of conditions or diseases. For example, forthe treatment of neuropathic pain or neuropathy pruritus in HIV-infectedpatients, it is well known that the intracellular concentration ofglutathione, the principle intracellular thiol anti-oxidant may bedrastically reduced to a point that further harm is caused to thepatient. Such glutathione depletion is believed to exacerbate many ofthe inflammatory pathways that contribute to the potentially intensepruritus and burning pain that accompanies HIV infection and HIVtherapy. Since administration of either cysteine or, especially NAC isknown to greatly increase intracellular glutathione, treatment ofHIV-induced neuropathy is one of many examples in which it may betherapeutically preferable to use a complex variant with more then onefunctional cysteine group.

The compositions of the present disclosure are useful in treating pain,pruritis, inflammation and irritation. For example, they are useful forthe following: 1) treating keratinized skin due to: acute sensoryirritation (caused by allergies, insect bites venomous pain, etc.);delayed reactions (caused by poison ivy, nickel allergy, diseases suchas atopic dermatitis, psoriasis); ionizing radiation (caused by sunburn,therapeutic xrays); and chemically induced irritants (such as cleaningsupplies, depilatory treatments, gasoline.) and 2) treating neuropathicpain such as post-herpetic neuralgia, shingles, nerve damage, nerveoversensitization, stump pain, diabetic neuropathy, etc.

Other examples of conditions in which the present compositions areuseful include, for example, herpes, HIV, itching, inflammation,irritation of the eyes, contraceptive irritation, thermal burns, skindamage, oral irritation, radiation, chemical burns, wounds, diabeticulcers, etc.

EXAMPLES

The examples that follow demonstrate the ability of a combination ofstrontium, a polyhydroxyphenol and a cysteine-based anti-oxidant totreat pain and pruritus caused by a variety of conditions, some thatoccur in response to an acute injury or stimulus, others that havechronic and/or neuropathic origins. As previously described, the pain orpruritus-transmitting nociceptors that are suppressed by thesecompositions occur throughout the body and their most peripheral endingsline the outmost viable surfaces of keratinized skin and epithelialsurfaces covered by mucous membranes in the eye, the mouth, throat,esophagus and gastrointestinal tract, the respiratory and genitourinarytracts.

Example 1 below describes the use of the complexes described herein totreat pain in the mouth is a particularly important indicator that suchcompositions will be an effective pain treatment for many other painfuloral conditions including oral and throat ulcers due to to infection,trauma, chemical irritant exposure, malignancy, for example, and painthat occurs in the throat (a ‘sore throat’), aphthous ulcers and andinfections that occur in and around the nociceptors themselves as inHerpes simplex infections.

In all these conditions, there are many different conditions and stimulithat activate Type C nociceptors nociceptors. No matter what proximalstimulus causes TCN activation, there are only two responses that canoccur, a painful sensation most often described as burning, stinging ortingling, itching or on occasion both of these sensations. As Examples 1and 2 below demonstrate, the complexes of the present disclosure arehighly effective at suppressing the pain caused by physical trauma tothe oral cavity, the mucosa, teeth, bone and surrounding structures dueto cracked teeth, and from subsequent extraction of two adjacent molarsthat caused severe physical trauma from subsequent surgical excision ofgum mucosa, tooth extraction and excision of the tooth root adherent tothe bone of the tooth socket and sewing of the, and trauma anddestruction of the pain-sensing nerves that innervate tooth pulp, aswell as pain sensing nerves in the adjacent bone and soft tissues.

The extraction of these molars and accompanying surgical proceduresresulted in activation of not only nociceptors in the teeth, gums,mucosa and bone, but as occurs in all trauma and inflammation,neutrophils were rapidly attracted to the site of bleeding and traumaand were activated to prevent normal bacterial flora from causinginfection of the surgical site. In such a surgical procedure withaccompanying physical trauma, most if not all of innate and adaptiveimmune and inflammatory pathways that are known to trigger pain werestrongly activated. The fact that a topical treatment with the complexesof the present disclosure produced such rapid and complete pain reliefstrongly suggests that it will also be an effective pain reliever inmany other painful conditions in the oropharynx, and in pain produced bytrauma or other inflammation-inducing processess in other portions ofthe body. It is important to note that the presence or absence of akeratinized layer of cells on the tissue that is being treated has nobearing or influence on the ability of the complexes of the presentdisclosure to effectively treat pain, pruritun or related nociceptivesensations. The fact that nociceptors in general and Type C Nocieptorsin particular have essentially the same functions, properties andabilities to transduce danger signals into calcium-encoded pain andpruritic sensations suggests that such nerves will have similar, if notessentially identical responsiveness to the therapeutic effects of thecomplexes of the present disclosure. While the presence or absence of akeratinized layer of cells will influence the rate and degree ofpenetration of a topically-applied treatment like the complex of thepresent disclosure, it will not appreciably affect the ability of thecomplex to suppress pain, pruritus or other nociceptive sensations orneurogenic inflammatory reactions.

As demonstrated by the examples herein, the complexes of the presentdisclosure are especially effective at suppressing the pain that occursin response to physical manipulation or trauma to the teeth, and thetooth-bone interactions that result in the strong adherence of teeth totheir bony sockets. Such trauma occurs especially in tooth manipulationssuch as orthodontic procedures, especially those involving braces orother physical wires, attachments or devices that have as a therapeuticgoal straightening or otherwise aligning or moving teeth. Pain fromphysical trauma to the face, skull, mouth and oropharynx from accidents,surgery or disease will also be particularly responsive to thepain-reducing benefits of the complexes taught herein.

Example 1 Oral Delivery

A 59 year old male experienced two cracked molars (lower left rear-mostand adjacent) that required two temporary crowns to be installed prior.Neither crowns were completely liquid tight and liquids ingestedpenetrated under the crown and directly contact the exposed tooth pulpnerves in both molars.

Within about a minute eating dill pickles one day after the crowns wereinstalled, the subject experienced intense and constant pain. On a 0 to10 point pain scale ( ) is the worst pain possible), the pain levelincreased to a 10 within 5-6 minutes, was constant and seemed tooriginate from both molars and the gum and cheek for several inchessurrounding the molars. After 10 minutes, the pain remained a 10 and itsubsided after about 60 minutes to a 0.

To compare the relative ability of 6% elemental strontium only or 4%strontium+Gallic Acid+NAC, the subject ingested another dill pickle andthe pain returned in a manner and quality identical to the descriptionabove.

The 6% strontium spray was applied by teaspoon and used to saturate bothmolars with a vigorous swishing action to force the liquid between andaround the crowns. The liquid was then held in place by the tongue.After about 60 seconds, a second application by teaspoon was applied andonly held with the tongue for 60 seconds.

The pain level that was at a 10 did not change for 2-3 minutes, thenover 4-5 minutes was reduced to a 6-7, a noticeable andpatient-appreciated pain reduction, yet too intense to tolerate over along period of time. As for the first challenge. During minutes 10-12,the pain returned to 10.

After rinsing the mouth with water, the subject then applied 4%strontium+Gallic Acid+NAC in the manner described for strontium alone.For the first 4-5 minutes, there was no change in the pain. Startingabout minutes 5-6, the pain started to diminish and by 7-8, it wasreduced by 3-4 points to a 6-7. Within the next 3-4 minutes, the paindiminished to a 0—it was completely gone. The pain remained at 0 level.

During the next consecutive 4 nights, the subject re-experiencedrecurrences of pain in the two molars, apparently triggered by a rangeof spicy foods or due to unidentified foods. In each case, the paincommenced within minutes of eating dinner, typically pre.cooked foods.The pain had a uniform profile, quality and time course and reached thesame intense, intolerable 10 level of pain.

Each night the subject waited about 5 minutes, then treated the sitewith the 6% strontium-only formulation, followed with the 4%strontium+Gallic Acid+NAC. The response to the 6% strontium wasremarkably consistent. The pain reduction always occurred within thefirst 6-8 minutes and was reduced to a maximum of 6-7. By 10 minutesafter treatment, the pain always returned to a 10-level.

One night, the 6% strontium-only treatment was repeated without rinsingafter the pain returned to 10 (2-3 minutes after the first treatment)and no cumulative or enhanced anti-pain benefit was observed. With thistwo-time strontium treatment, the pain was never reduced below a level 7or 8, a noticeable but intolerable level.

After rinsing the mouth with water, the strontium+Gallic Acid+NACtreatment similarly demonstrated a highly consistent pattern ofresponse. Within 10 to 12 minutes after treatment, the pain wascompletely gone (a 0 level) and remained gone for the remainder of eachnight.

No side effects including numbness, change of taste, tactile sensationor tongue motor strength was observed.

Several weeks later, both of the broken molars were extracted in the 59year old male in preparation for later implants. Hydrocodone oral painmedications were prescribed and used up to the maximum recommended doseand frequency. Acetaminophen was also used in conjunction with thehyodrocodone.

One day after the extractions, the subject consumed soup that triggeredintense 10-level pain within 1-2 minutes. The pain remained constant andlevel 10 and extended throughout the lower left jaw area.

The subject rinsed the mouth and used a dentist supplied washing agentto bathe the surgical sites without effect on the pain.

The subject then applied the 6% strontium-only formulation and atminutes 6-7, experienced a 1-2 point pain reduction—noticeable, butclinically ineffective.

The strontium+Gallic Acid+NAC was then applied in as in the previousmanner and held in the surgical area with the tongue. During the first4-5 minutes there was no pain reduction or increase of pain. At aboutminute 5, the pain started to diminish and by minutes 8-9 reached a 5level of pain, a substantial reduction. No further pain reduction wasobserved in the next 2-3 minutes, and the strontium+Gallic Acid+NAC wasreapplied. After about 4-5 minutes, the pain continued it's reductionand after about 7-8 additional minutes, reached 0-level—complete paincessation. The pain remained completely gone for the rest of the nightin into the next day.

During the next week, the 59 year old subject was unable to avoid eatingfoods that did not trigger the pain, probably because the extractionsites were still slightly bleeding/oozing and were thus directlyaccessible to chemical irritants in foods.

Each night the pain recurred with minutes after consuming either solidfood or liquids and reached the same unbearable intensity. Each nightthe treatment protocol listed above was repeated: 6% strontium—onlyformulation treatment first; mouth rinse; and 4% strontium+GallicAcid+NAC treatment afterwards. For the next 5 nights, the pain recurred,reached the same intense level (10 using our scale), and at best, the 6%strontium only treatment reduced the pain by at most 3 points for 2-3minutes, after which it returned to the previous 10 level.

The treatment with strontium+Gallic Acid+NAC was similarly reproducible.After the strontium only treatment and rinse, the strontium+GallicAcid+NAC required 1-2 treatments during a 12-15 minute time after whichthe pain was always completely eliminated and remained absent for theremainder of the night and the next day. Within a week after theextractions, the extraction sites healed sufficiently to becomenon-sensitive to food-derived pain inducers.

Example 2 Neuropathic Pain Due to Nerve Compression

An 85 year old woman with severe macular degeneration, but otherwise ingood health had experienced mild, bilaterally symmetric burning pain inboth of her feet, slightly more intense on the bottom of her toes, butvery evident and bothersome on the tops of both toes. The burning painhad been continuous, all day and all night and during the last 3 yearsand was be made worse with walking. Typically at the end of a day theburning pain was at its worst. By all accounts it was relatively mild inthat it did not bother her or interfere with walking or other activitiesduring the day, but after a year or so after it started, she had to takeher shoes off at night due to excessive burning.

In the last year, the intensity of the burning slowly increased to thepoint where her pain at night increased sufficiently so that she wasunable to wear shoes with straps that wrapped around her toes—only fullyunclosed shoes that did not contact her toes were tolerable, along withsocks that provided cushioning. During the last 6 months, the intensityof the burning pain slowly increased so that she was unable to walk atnight after dinner due to the burning pain. The pain during the day wasnot greatly increased nor was it excessively bothersome. The painstarted to keep her from sleeping at night due to its constancy leadingto her reduced daily walking.

The pain was, as it had always been, constantly present, essentiallyequal in intensity and distribution in both feet and worse at night andwas not accompanied by any visible skin changes, redness or rash. Theskin with the burning sensation also had numbness that extended overmuch of her feet in a bilaterally symmetrically manner.

She had no risk factor to explain the numbness or burning in other thenmild, chronic back pain with maximum pain emanating from the L-4, L-5,S-1 spinal roots. Since these nerves also innervate the top and bottomof feet, including the toes, the subject's physician suspects that thereported symptoms are due to compression of the spinal nerves at the L-4to S-1 level and that the cause of the burning pain is chronic nervecompression that produced nerve damage, especially to Type C Nociceptorsthat transmit burning sensations. The resultant condition is a nervecompression neuropathic pain state.

The subject tested two formulations in a double-blind controlled manner.The product applications and data recording were performed by a retiredaeronautical engineer.

At 8 PM both toes and the tops of both feet had the typical continuousburning pain sufficiently severe that shoes having any contact with thetops of her feet or toes were not worn. The pain levels were verysimilar.

Using a 0-10 point visual-analog scale, the subject was instructed torank the foot with the most severe burning as a 10 and to assign thecontralateral foot a score to reflect its pain level relative to the 10level foot.

Her assignment was: Burning Pain Intensity in Left Foot—10; in RightFoot—8.

The Right Foot was then treated with a coded product labeled ‘A’ (the 4%strontium hydrogel) and the skin of the toes and the entire top of thefoot was covered with the test material. No immediate effect wasobserved. Over the next 15-20 minutes, the burning pain continuouslyreduced from an 8 to a 5-6 level of pain. At 30 minutes treatment, thepain returned.

The Left Foot was then treated with a 2% strontium+Gallic Acid+NAC gelformulation in a manner identical to the Left Foot. Upon treatment, thepain remained a 10.

Within 1 minute after application, the pain reduced from a 10 to a 5 andby 5 minutes in was gone, a score of 0 and remained 0.

The next day at 8 PM, the Left foot had a 0 score and the subjectreported that the pain was gone throughout the night . . . the firstnight in over three years that was pain free.

The right foot that had been treated with the 4% strontium gel had aburning pain score of 8 and had the score throughout the night, thesubjects usual experience.

The Right foot was then treated with 2% strontium+Gallic Acid+NAC aspreviously described and within 5 minutes the pain was gone—a score of0.

The numbness was not affected in either foot.

During the next 6 months, both feet have remained entirely pain free andthe subject has been wearing shoes with toe wrap around bands and othershoes that directly contact the upper part of the feet and the toes withcomfort. There has not been one recurrence of pain in either foot andthe patient has resumed a normal ability to walk and wear the shoes ofher choice. The numbness in both feet is unchanged and is the same asbefore the treatments occurred.

Example 3 Bracioradial Pruritis

A 40 year old male suffered from brachioradial pruritus for over 20years, a neuropathic condition that is believed to be caused bycompression of cervical nerves that innervate the mid-back and arms. Beexperienced moderate to severe itching typically most intense on hisarms, neck and shoulders. Treatment with topical anti-itch drugsincluding 1% hydrocortisone, menthol-containing courter-irritantsprovided no anti-itch benefit. Topical diphenhydramine provided limitedbenefit only when the itching was mild.

During the last several years, the subject treated his condition witheither strontium alone (4% or 6% elemental strontium) and with a sprayformulation of strontium+Gallic Acid+NAC. A single treatment of severeitch with 6% elemental strontium alone provided limited anti-itchbenefits. Reapplication 3 or 4 times over a 10-20 minute periodincreased that anti-itch benefit and reduced the itching by about 50%.When the 4% strontium+Gallic Acid+NAC was applied to severely itchingskin, the severity of itching was typically reduced by 80% to 90% withinabout a minute after a single spray, and sometimes, the itching wascompletely eliminated. If itching remained, a second spray eliminatedthe remaining itching.

Subsequent blinded tests were performed in which either 4% strontiumonly or 6% strontium only was directly compared to 4% strontium+GallicAcid+NAC. Since the subject's brachioradial pruritus typically produceditching of approximately equal intensity on both arms in abilaterally-symmetrical pattern, strontium alone was applied to one armand strontium+Gallic Acid+NAC was applied to the contralateral arm in adouble-blinded manner and itch severity was reported by the subject.Repeated studies of this type demonstrated that the strontium+GallicAcid+NAC was always substantially more effective then strontium aloneand typically suppressed itching by 80% to 100% within several minutes.In contrast, strontium alone provided only limited relief with moderateto severe itch. The strontium+Gallic Acid+NAC also produced asubstantial anti-itch benefit of much longer duration and frequentlysuppressed itching for more then a 24 hour period. Strontium aloneprovided only limited anti-itch benefit that typically lasted onlyseveral hours, at most.

Example 4 Burn Pain

A female was scalded by hot tea over the whole of her left hand and onher forearm up to about 4 inches above her wrist. A spray ofstrontium+Caffeic Acid+NAC was applied between half a minute and aminute after the incident. The intense pain started to recede shortlyafter application (probably about 30 seconds) and the redness of thehand and arm quickly became less angry. Within about 5 minutes, thesubject no longer felt any discomfort and the redness had disappeared.There was no need for any further application of the spray and theredness did not return and she suffered no blistering or bubbling. Herleft hand was tender for a while in the sense that she used the otherhand to carry things for the rest of the evening. The incident occurredat about 7.30 in the evening. The following day when she woke up, herhand was completely normal.

Example 5 Wasp Sting

An adult male subject observed a wasp sting on the back of his righthand. Within about 30 seconds, the subject experienced increased burningpain and accompanying mild itching that rapidly increased in severity.Swelling and redness rapidly developed over the next 2-3 minutes and thepain intensified to an unbearable level. The subject then applied thesame spray from Example 3. Within the first several minutes the pain wasunaffected. During the next 5 minutes, the pain was reduced and afterapproximately 6-7 minutes the pain was completely gone. There was novisible reduction in the redness or the swelling that produced a swollencircular area of skin about 2-3 inches in diameter with a height ofabout ¼ of an inch. The pain and itching did not return and over thenext hour or so, the swelling and redness diminished and disappeared.

Example 6 Chronic Pruritis

A 72 year old adult male subject suffered from a chronic pruritic drypatch of skin on his right ankle that had been itching more or lessconstantly for several months. Periodic treatment with a 4% elementalstrontium-containing hydrogel or a 6% elemental strontium-containingaqueous spray formulation provided moderate itch relief that typicallylasted several hours, after which the itching returned. Treatment withthe spray described in Example 3 completely reduced the itching withinseveral minutes that lasted for over a day. Subsequent re-treatment withthe same spray produced similar and complete itch relief that lastedfrom about 12 hours to over 24 hours.

Example 7 Synthesis of Thioester Bonded Gallic Acid and NAC

Synthesis 1: The gallic acid carboxyl group was attached to the NACsulfhydryl group to create a thioester bond. Gallic acid was reactedwith acetic anhydride and sulfuric acid to protect the three hydroxylgroups on the benzene ring. The resulting compound,3,4,5-triacetoxybenzoic acid (compound A), was precipitated in water,filtered and dried under vacuum.

Synthesis 2: Compound A was reacted with oxalyl chloride anddichloromethane to substitute chlorine for the remaining hydroxyl group.The resulting compound, which was the corresponding acid chloride,(compound B) was purified using toluene and dried under vacuum.

Synthesis 3: Compound B was reacted with 1H-benzo[d][1,2,3]triazole inacetonitrile. The resulting compound,5-(1H-benzo[d][1,2,3]triazole-1-1carbonyl)benzene-1,2,3-triyl triacetate(compound C), was filtered with cold water and dried under vacuum.

Synthesis 4: Compound C in 1,4 dioaxane was reacted with N-acetylcysteine, potassium acetate, and water. The resulting compound (compoundD), was acidified with hydrochloride, washed with ethyl acetate, andevaporated.

Synthesis 5: Compound D was reacted with water and ammonium hydroxide tohydrolyze the acetyl protective groups added in the first synthesis. Theresulting compound is the thioester bound gallic acid and NAC (GA:NAC)

The GA:NAC was reacted with strontium nitrate. The final compound,strontium tripartite with thioester bond (Sr:GA:NAC), was precipitatedout using acetone and vacuum dried.

Example 8 Octanol-Water Partition Co-Efficient, Determination of cLogP

The strontium tripartite with thioester bond compound was partitionedbetween octanol and water in order to determine the water solubilityproperties of the compound. The partition co-efficient, cLogP, wasdetermined by using high performance liquid chromatography (HPLC). ThecLogP for Sr:GA:NAC was −0.209, which means that the final compound hassimilar solubility to ethanol.

Example 9 Cleaving of Thioester Bond Using Human Enzymes

The strontium tripartite with thioester bond compound was subjected toenzymatic cleavage with three different enzymes, human carboxylesteraseI (CES1), human carboxylesterase II (CES2), and S9 liver microsomesenzyme.

For each of the three enzymes evaluated, Sr:GA:NAC was added to foursample tubes, A, B, C, and D. Enzyme was added to tubes A and B andgallic acid was added to tube D. The samples were tested by monitoringthe UV counts at time points 5, 60, 180, 360, 540, 1380 minutes by HPLCusing a C18 column.

The results demonstrated that all three enzymes cleaved the thioesterbond to release NAC and gallic acid.

The embodiments discussed above are provided to give those of ordinaryskill in the art a complete disclosure and description of how to makeand use the embodiments of the methods, and are not intended to limitthe scope of what the inventor regards as his invention. Modificationsof the above-described modes (for carrying out the invention that areobvious to persons of skill in the art) are intended to be within thescope of the following claims. All publications, patents, and patentapplications cited in this specification are incorporated herein byreference as if each such publication, patent or patent application werespecifically and individually indicated to be incorporated herein byreference.

1-78. (canceled)
 79. A composition comprising a complex of: a divalentcationic strontium moiety; a cysteine-based anti-oxidant moiety selectedfrom the group consisting of: cystine, N-acetyl cysteine (NAC), N-acetylcysteinate, N-acetyl cystine, N,S-diacetylcysteine, and esters thereof;and a polyhydroxyphenol moiety selected from the group consisting of:gallic acid, caffeic acid, quercetin, luteolin, epigallocatechingallate, epigallocatechin, epicatechin gallate, genistein, myricetin,and esters thereof; in a suitable carrier vehicle, wherein thecysteine-based anti-oxidant and the polyhydroxyphenol moiety areconjugated together by a cleavable bond.
 80. The composition accordingto claim 79, wherein the cysteine-based anti-oxidant moiety is N-acetylcysteine (NAC) or esters thereof.
 81. The composition according to claim79, wherein the polyhydroxyphenol moiety is gallic acid or estersthereof.
 82. The composition of claim 79, wherein the cysteine-basedanti-oxidant moiety is N-acetyl cysteine (NAC) or esters thereof and thepolyhydroxyphenol moiety is gallic acid or esters thereof.
 83. Thecomposition of claim 79, wherein the strontium moiety is a strontiumsalt selected from the group consisting of: strontium chloride,strontium chloride hexahydrate, strontium sulfate, strontium carbonate,strontium nitrate, strontium hydroxide, strontium hydrosulfide,strontium oxide, strontium acetate, strontium glutamate, strontiumaspartate, strontium malonate, strontium maleate, strontium citrate,strontium threonate, strontium lactate, strontium pyruvate, strontiumascorbate, strontium alpha-ketoglutarate, and strontium succinate. 84.The composition according to claim 79, wherein the cleavable bond isselected from the group consisting of: a peptide bond, an ester bond, athioester bond, an enzymatically cleavable bond, a disulphide bond, anda pH dependent bond.
 85. The composition according to claim 84, whereinthe cleavable bond is a thioester bond.
 86. The composition according toclaim 79, further comprising a polymer.
 87. The composition according toclaim 86, wherein the polymer is selected from the group consisting of:polyvinylpyrrolidone (PVP), cyclodextrins, carrageenan, alginic acid,xanthan gum, sulfated polysaccharides, pentosan polysulfate, chondroitinsulfate, dextran sulfate and heparin sulfate.
 88. A compositioncomprising a complex of: a divalent cationic strontium moiety; acysteine-based anti-oxidant moiety; and a polyhydroxyphenol moiety;wherein the cysteine-based anti-oxidant and the polyhydroxyphenol areconjugated together by a thioester bond.
 89. The composition accordingto claim 88, wherein the cysteine-based anti-oxidant moiety is selectedfrom the group consisting of: cystine, N-acetyl cysteine (NAC), N-acetylcysteinate, N-acetyl cystine, N,S-diacetylcysteine, and esters thereof.90. The composition according to claim 88, wherein the polyhydroxyphenolmoiety is selected from the group consisting of: gallic acid, caffeicacid, quercetin, luteolin, epigallocatechin gallate, epigallocatechin,epicatechin gallate, genistein, myricetin, and esters thereof.
 91. Thecomposition according to claim 88, wherein the strontium moeity is astrontium salt selected from the group consisting of: strontiumchloride, strontium chloride hexahydrate, strontium sulfate, strontiumcarbonate, strontium nitrate, strontium hydroxide, strontiumhydrosulfide, strontium oxide, strontium acetate, strontium glutamate,strontium aspartate, strontium malonate, strontium maleate, strontiumcitrate, strontium threonate, strontium lactate, strontium pyruvate,strontium ascorbate, strontium alpha-ketoglutarate, and strontiumsuccinate.
 92. A composition comprising a complex of a strontium nitratemoiety, an N-acetyl cysteine (NAC) moiety, and a gallic acid moiety;wherein the NAC and the gallic acid are conjugated together by athioester bond.
 93. A method of treating pain in a subject comprisingtopically administering the compound of claim 79 to the subject.
 94. Amethod of treating pruritus in a subject comprising topicallyadministering the compound of claim 79 to the subject.
 95. A method oftreating pain in a subject comprising topically administering thecompound of claim 88 to the subject.
 96. A method of treating pruritusin a subject comprising topically administering the compound of claim 88to the subject.
 97. A method of treating pain in a subject comprisingtopically administering the compound of claim 92 to the subject.
 98. Amethod of treating pruritus in a subject comprising topicallyadministering the compound of claim 92 to the subject.